Publications by authors named "Mohiuddin M Taher"

33 Publications

Identification of PKHD1 mutations in Brain, Breast and Rectal tumors by Next Generation DNA Sequencing.

Gulf J Oncolog 2021 Jan;1(35):42-53

Departments of Medical Genetics, Umm-Al-Qura University, Makkah, Saudi Arabia.

Introduction: It is well established that the PKHD1 mutations are associated with autosomal recessive polycystic kidney disease (ARPKD). Although, PKHD1 mutations are also detected in certain cancer types, to our knowledge in rare tumors such as, atypical teratoid rhabdoid tumor (ATRT), primary neuro-ectodermal tumor (PNET), atypicalchoroid plexus papilloma (a-CPP), amelanotic ano-rectal melanoma (AMM), and breast phyllodes tumors PKHD1 mutations profiling is not reported.

Methods: In order to determine the PKHD1 gene mutation patterns in the brain, rectal, and breast tumors we have analyzed these tumor DNA by Ion Proton Next generation DNA sequencing.

Results: Next-generation DNA sequencing on Ion Proton identified unique and common missense mutations in the brain, breast and ano-rectal tumors. All mutations were benign, and only one pathogenic mutation in p. (Cys3346Arg) found in AMM tumor. In phyllodes tumor of breast, two unique missense variants were detected (rs113562492) p. (Met2841Val); and (rs137972270) in p. (Arg589Cys) and these variants are not present in other tumors tested. The variant rs137972270 was reported only in two cases sofar in ClinVar database. Missense variants such as rs115045643, rs116809571, rs115338476, and rs76895755 are found only in PNET, and a variant rs62406032 in a-CPP, another one rs35445653 in ATRT cases were unique for these tumors, which are not present in other tumors. Several synonymous and intronic variants of PKHD1 gene were also found in these tumors. A synonymous variant p. (Asp395Asp), rs1896976 and two intronic SNPs viz., rs1326605, and rs1571084 were found in all tumors tested. The SNP rs9395699 in IVS66 was found uniquely in IPC breast tumor only in this study. Allele coverage, allele ratio, p-value, Phred qual score, sequencing coverage, alleles frequencies were also analysed, the p-values and Phred quality score were significantly higher.

Conclusion: These tumors did not have any insertion/ deletion mutations, nonsense, or truncated mutations in it. The screening of PKHD1 gene revealed signature mutations for the solid tumors studied by NGS method. This investigation may help in understanding these tumor pathology at molecular level.
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January 2021

Next Generation Exome Sequencing of Pediatric Asthma Identifies Rare and Novel Variants in Candidate Genes.

Dis Markers 2021 8;2021:8884229. Epub 2021 Feb 8.

Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.

Multiple genes have been implicated to have a role in asthma predisposition by association studies. Pediatric patients often manifest a more extensive form of this disease and a particularly severe disease course. It is likely that genetic predisposition could play a more substantial role in this group. This study is aimed at identifying the spectrum of rare and novel variation in known pediatric asthma susceptibility genes using whole exome sequencing analysis in nine individual cases of childhood onset allergic asthma. DNA samples from the nine children with a history of bronchial asthma diagnosis underwent whole exome sequencing on Ion Proton. For each patient, the entire complement of rare variation within strongly associated candidate genes was catalogued. The analysis showed 21 variants in the subjects, 13 had been previously identified, and 8 were novel. Also, among of which, nineteen were nonsynonymous and 2 were nonsense. With regard to the novel variants, the 2 nonsynonymous variants in the gene (: p.C519W and : p.G520W) were presented in 4 cases, and a nonsynonymous variant in the gene (: p.A45V) was identified in 3 cases. The variants we found in this study will enrich the variant spectrum and build up the database in the Saudi population. Novel eight variants were identified in the study which provides more evidence in the genetic susceptibility in asthma among Saudi children, providing a genetic screening map for the molecular genetic determinants of allergic disease in Saudi children, with the goal of reducing the impact of chronic diseases on the health and the economy. We believe that the advanced specified statistical filtration/annotation programs used in this study succeeded to release such results in a preliminary study, exploring the genetic map of that disease in Saudi children.
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http://dx.doi.org/10.1155/2021/8884229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888305PMC
February 2021

A unique case of multiple calvarial hemangiomas with one large symplastic hemangioma.

BMC Neurol 2021 Jan 19;21(1):29. Epub 2021 Jan 19.

Department of Medical Genetics, Umm-Al-Qura University, Makkah, Saudi Arabia.

Background: Symplastic hemangioma is a benign superficial abnormal buildup of blood vessels, with morphological features which can mimic a pseudo malignancy. A few cases have been reported in the literature. We report here, a unique case of calvarial symplastic hemangioma, which is the first case in the calvarial region.

Case Presentation: A 29-year-old male patient, with a left occipital calvarial mass since childhood, that gradually increased in size with age, was associated with recurrent epileptic fits controlled by Levetiracetam (Keppra), with no history of trauma. He presented to the emergency room with a recent headache, vomiting, frequent epileptic fits and a decrease in the level of consciousness 1 day prior to admission. A CT scan showed three diploic, expansile, variable sized lytic lesions with a sunburst appearance; two that were biparietal, and one that was left occipital, which were all suggestive of calvarial hemangiomas. However, the large intracranial soft tissue content, within the hemorrhage of the occipital lesion was concerning. The patient had refused surgery over the years; however, after the last severe presentation, he finally agreed to treatment. The two adjacent, left parietal and occipital lesions were treated satisfactorily using preoperative embolization, surgical resection, and cranioplasty. Histopathology revealed cavernous hemangiomas, in addition to symplastic hemangioma (pseudo malignancy features) on top at the occipital lesion. The right parietal lesion was not within the surgical field; therefore, it was left untouched for follow-up.

Conclusions: Histopathology and radiology examinations confirmed the diagnosis as symplastic hemangioma, on top of a pre-existing cavernous hemangioma. To the best of our knowledge, this is the first case of a calvarial symplastic hemangioma, which we report here.
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http://dx.doi.org/10.1186/s12883-021-02053-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814591PMC
January 2021

The Co-existence of ADHD With Autism in Saudi Children: An Analysis Using Next-Generation DNA Sequencing.

Front Genet 2020 15;11:548559. Epub 2020 Dec 15.

Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders. Several studies have confirmed the co-existence of other neuropsychiatric disorders with ADHD. Out of 106 individuals suspected to have ADHD, eight Saudi Arabian pediatric patients were diagnosed with ADHD using a dual assessment procedure based on highly significant scores from the international criteria for diagnosis; (full form DMS) DSM-5. Then, these patients were examined for the co-existence of autism and ADHD using different international diagnostic protocols. Four patients with combined ADHD and autism and four ADHD patients without autism were examined for the presence of genetic variants. Six variants (chr1:98165091, chr6:32029183, chr6:32035603, chr6:32064098, chr8:2909992, chr16:84213434) were identified in 75% of the patients with ADHD and autism, indicating that these genes may have a possible role in causing autism. Five variants (The chr2:116525960, chr15:68624396, chr15:91452595, chr15:92647645, and chr16:82673047) may increase to the severity of ADHD. This study recommends screening these eleven variants in ADHD cases and their relevant controls to confirm the prevalence in the Saudi population. It is recommended that future studies examine the 11 variants in detail.
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http://dx.doi.org/10.3389/fgene.2020.548559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770135PMC
December 2020

EGFRvIII expression and isocitrate dehydrogenase mutations in patients with glioma.

Oncol Lett 2020 Dec 23;20(6):384. Epub 2020 Oct 23.

Department of Radiation Oncology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.

Molecular pathology and personalized medicine are still being evolved in Saudi Arabia, and genetic testing for the detection of mutations as cancer markers have not been established in the diagnostics laboratories in Saudi Arabia. The aim of the present study was to determine the prevalence of isocitrate dehydrogenase (IDH1 and IDH2) mutations and epidermal growth factor receptor variant (EGFRv)III transcript expression in Saudi Arabian patients with glioma. Out of 117 brain tumors tested by reverse transcription-quantitative PCR for EGFRvIII, 41 cases tested positive. In the glioblastoma (GBM) category, 28/55 tumors were positive, in astrocytoma tumors 5/22, and in oligodendrogliomas 4/13 cases were positive respectively. EGFRvIII transcript was sequenced by capillary electrophoresis to demonstrate the presence of EGFRvIII-specific junction where exons 2-7 were deleted. In the present study 106 tumors were sequenced for IDH1 exon-4 mutations using the capillary sequencing method. The most common substitution missense mutation c.395G>A was found in 16 tumors. In the case of adamantinomatous craniopharyngioma, a novel missense mutation in c.472C>T was detected in IDH2 gene. Using next-generation sequencing (NGS), 74 tumors were sequenced for the IDH1 gene, and a total of 8 missense variants were identified in 36 tumors in a population of Saudi Arabia. The missense mutation (c.395G>A) was detected in 29/36 of tumors. A novel intronic mutation in c.414+9T>A was found in 13 cases in the IDH1 gene. In addition, one case exhibited a novel synonymous mutation in c.369A>G. Eleven tumors were found to have compound mutations in the IDH1 gene. In IDH2 gene, out of a total of 16 variants found in 6 out of 45 tumors, nine were missense, five were synonymous and one was intronic. This is the first report from Saudi Arabian laboratories analyzing glioma tumors for EGFRvIII expression, and the first study from Saudi Arabia to analyze IDH mutations in gliomas using the capillary and NGS methods.
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http://dx.doi.org/10.3892/ol.2020.12247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656109PMC
December 2020

Association between HindIII (rs320) variant in the lipoprotein lipase gene and the presence of coronary artery disease and stroke among the Saudi population.

Saudi J Biol Sci 2020 Aug 24;27(8):2018-2024. Epub 2020 Jun 24.

Department of Cardiac Surgery, Monzino Heart Center, University of Milan, Milan, Italy.

Lipoprotein Lipase (LPL) is known to be a key enzyme for lipid metabolism specifically in an enzymatic glycoprotein which provide tissues without fatty-acids and eliminates triglycerides (TG) by the circulation. Mutations in LPL were proven to cause alteration in fractions within lipoprotein, causing the development of atherosclerosis which predispose to weakening coronary artery disease (CAD) and stroke. We examined the linkage between genetic variant III in LPL on lipoprotein fractions, stroke occurrences and CAD. In this case-control study, we have recruited 315 CAD cases and 205 age-matched controls. A total of 520 genomic DNA was digested with the purified PCR products for restriction fragment length polymorphism with III restriction enzyme. The distribution of genotypes in a decreasing order were TT, 148 (47%), GT 135 (42.9%) and GG 32 (10.2%) in CAD groups of the study while the pattern in controls were GT 91 (44.4%), TT 86 (42%) and GG 28 (13.7%). None of all the allele or genotype frequencies were found to be significant in our study (p greater than 0.05), while the biochemical levels for both TG and LDL-c were shown to be prone in CAD patients when compare with the controls. Furthermore, the occurence of strokes were more in CAD groups vs. controls: 72 (22.9%) vs. 7 (3.4%) [p 0.000]. This could indicate the influence of III variant on plasma lipid levels, and the possibility of considering it a risk factor for atherosclerosis leading to CAD and stroke occurrence.
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http://dx.doi.org/10.1016/j.sjbs.2020.06.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376116PMC
August 2020

Xanthomas Can Be Misdiagnosed and Mistreated in Homozygous Familial Hypercholesterolemia Patients: A Call for Increased Awareness Among Dermatologists and Health Care Practitioners.

Glob Heart 2020 02 28;15(1):19. Epub 2020 Feb 28.

Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah Al Mukarramah, SA.

Background: Familial hypercholesterolemia (FH) is an autosomal dominant inherited genetic disorder and results in the development of coronary artery disease (CAD). Clinical diagnosis of homozygous HH patients is usually straightforward because persistent hypercholesterolemia can produce xanthoma and corneal arcus. However, xanthoma may also be misdiagnosed as skin lesions and could therefore be mistreated. The aim of this case study report is to highlight the plight of patients with FH as means of raising awareness of the condition among dermatologists and health care practitioners, also to determine the genotype-phenotype correlation in severely affected homozygous FH proband patients.

Methods: Genetic screening of FH associated genes was performed by Ion Torrent next-generation sequencing and cascade screening by capillary sequencing.

Results: We present two clinical cases with prominent skin lesions seen in a dermatology clinic that were referred to plastic surgery for excision. Genetic testing was performed later, and confirmed common single nucleotide deletion variant (c.2027delG) in the alleles consequent to a frameshift mutation p.(G676Afs*33). In addition to the variant, two possibly damaging variants p.(L3313I) and p.(L1212M) and three damaging variants p.(R19*), p.(G83Q) and p.(S474*) in and genes respectively were identified. The gene variant p.(G83Q) was found to be novel, while others have been previously reported. Both patients were refractory to pharmacological therapies and are currently on lipoprotein apheresis (LA).

Conclusions: The present report indicates the need for increased awareness of FH, among the public and healthcare practitioners and supports the need for diagnostic screening and cascade genetic testing of this high-risk condition, which could ultimately lead to better prevention of CHD in this lethal condition.
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http://dx.doi.org/10.5334/gh.759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218775PMC
February 2020

Adamantinomatous Craniopharyngioma in an Adult: A Case Report with NGS Analysis.

Int Med Case Rep J 2020 21;13:123-137. Epub 2020 Apr 21.

Science and Technology Unit, Umm-Al-Qura University, Makkah, Saudi Arabia.

Purpose: Several recent studies have documented and mutations which are mutually exclusive for adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (PCP) tumors. This discovery is helpful in the development of novel targeted therapies in successful clinical trials with mutations in PCP cases. However, no such targeted therapy is available yet for ACP. Here, we report novel mutations, which are not previously reported, in a case of an adult ACP using NGS analysis.

Results: Patient DNA was sequenced using Ion PI v3 chip on Ion Proton. A total of 16 variants were identified in this tumor by NGS analysis, out of which four were missense mutations, seven were synonymous mutations, and five were intronic variants. In gene a known missense mutation in c.101G>T; in a known missense mutation in c.215C>G; and two known missense variants in , viz., in c.1173A>G; in exon 7, and in c.3128T>C; in exon 21, were found, respectively. Seven synonymous mutations were detected in this tumor, viz., in (rs11554137), in (rs7688609), in (rs1873778), in (COSM3760869), in (rs1050171), in (rs35775721), and in (rs1800861), respectively. Three known, intronic variants were found in genes, such as , and respectively. Also, a 3'-UTR and a splice site acceptor site variant in and genes were found in this tumor. We have shown allele coverage, allele ratio, and p-value, for all these mutations. The p-values and Phred quality score were significantly high for these variants.

Conclusion: As reported in previous studies, in ACP tumors we found a mutation by NGS analysis. The variants we detected were not known previously in ACP tumors. Finding the mutations in the ACP tumors may help develop targeted therapy for a subset of craniopharyngiomas with activating mutations. Clinical trials are in progress with specific inhibitors in advanced stages of many cancers.
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http://dx.doi.org/10.2147/IMCRJ.S243405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183340PMC
April 2020

Molecular Dynamics Simulation Reveals Exposed Residues in the Ligand-Binding Domain of the Low-Density Lipoprotein Receptor that Interacts with Vesicular Stomatitis Virus-G Envelope.

Viruses 2019 11 15;11(11). Epub 2019 Nov 15.

Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia.

Familial hypercholesterolemia (FH) is an autosomal dominant disease most often caused by mutations in the low-density lipoprotein receptor (LDLR) gene, which consists of 18 exons spanning 45 kb and codes for a precursor protein of 860 amino acids. Mutations in the LDLR gene lead to a reduced hepatic clearance of LDL as well as a high risk of coronary artery disease (CAD) and sudden cardiac death (SCD). Recently, LDLR transgenes have generated interest as potential therapeutic agents. However, LDLR packaging using a lentiviral vector (LVV) system pseudotyped with a vesicular stomatitis virus (VSV)-G envelope is not efficient. In this study, we modified the LVV system to improve transduction efficiency and investigated the LDLR regions responsible for transduction inhibition. Transduction efficiency of 293T cells with a 5'-LDLReGFP-3' fusion construct was only 1.55% compared to 42.32% for the eGFP construct. Moreover, co-expression of LDLR affected eGFP packaging. To determine the specific region of the LDLR protein responsible for packaging inhibition, we designed constructs with mutations or sequential deletions at the 3' and 5' ends of LDLR cDNA. All constructs except one without the ligand-binding domain (LBD) (pWoLBD-eGFP) resulted in low transduction efficiency, despite successful packaging of viral RNA in the VSV envelope, as confirmed through RT-PCR. When we evaluated a direct interaction between LDLR and the VSV envelope glycoprotein using MD simulation and protein-protein interactions, we uncovered Val119, Thr120, Thr67, and Thr118 as exposed residues in the LDLR receptor that interact with the VSV protein. Together, our results suggest that the LBD of LDLR interacts with the VSV-G protein during viral packaging, which significantly reduces transduction efficiency.
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http://dx.doi.org/10.3390/v11111063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893590PMC
November 2019

Primary Anorectal Amelanotic Melanoma: The First Case Report from Saudi Arabia.

Middle East J Dig Dis 2019 Jul 22;11(3):166-173. Epub 2019 May 22.

Department of Medical Genetics, Umm-Al-Qura University, Saudi Arabia.

Anorectal melanomas are exceptionally uncommon and only 30% of anorectal melanomas are amelanotic. We report here a case of an anorectal amelanotic melanoma in a female patient. An 84-year-old patient complained of anal mass for 3 months. On examination, there was a 7.0 cm mass prolapsing through the anus that was pale-pink in color. Abdominal, pelvic, and chest computed tomography (CT) showed rectal wall thickening with an eccentric polypoid soft tissue density mass, and left inguinal and presacral lymph node enlargement along with a small nodule in the lower lobe of the left lung, likely representing metastatic deposit. Microscopic examination revealed a piece of skin with hyperplastic squamous epithelium with surface ulceration. The dermis and underlining tissue were showing infiltration by malignant sheets and nests of ovoid and spindle shape cells with prominent nucleolus and high mitotic s. Immuno-staining for HMB-45, S-100, and Melan-A was positive, and it was negative for P63, CK 5/6, and Pan-CK, thus confirming it as an anorectal amelanotic melanoma, and not an epithelial tumor. This is the first case of an amelanotic anorectal melanoma reported from Saudi Arabia.
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http://dx.doi.org/10.15171/mejdd.2019.144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819967PMC
July 2019

Next generation DNA sequencing of atypical choroid plexus papilloma of brain: Identification of novel mutations in a female patient by Ion Proton.

Oncol Lett 2019 Nov 19;18(5):5063-5076. Epub 2019 Sep 19.

Department of Medical Genetics, Faculty of Medicine, Umm-Al-Qura University, Makkah 21955, Saudi Arabia.

Choroid plexus papilloma (CPP) is a rare benign tumor of the central nervous system that is usually confined to the cerebral ventricles. According to the World Health Organization, CPP corresponds to a grade I atypical CPP (a-CPP); however, it can become more aggressive and reach grade II, which can rarely undergo malignant transformation into a choroid plexus carcinoma (grade III). To the best of our knowledge, identification of these tumors mutations by next generation DNA sequencing (NGS) has not been yet reported. In the present study, NGS analysis of an a-CPP case was performed. Data were analyzed using Advaita Bioinformatics i-VariantGuide and Ion Reporter 5.6 programs. The results from NGS identified 12 novel missense mutations in the following genes: NOTCH1, ATM, STK36, MAGI1, DST, RECQL4, NUMA1, THBS1, MYH11, MALT1, SMARCA4 and CDH20. The PolyPhen score of six variants viz., DST, RECQL4, NUMA1, THBS1, MYHI1 and SMARCA4 were high, which suggested these variants represents pathogenic variants. Two novel insertions that caused frameshift were also found. Furthermore, two novel nonsense mutations and 14 novel intronic variants were identified in this tumor. The novel missense mutation detected in ATM gene was situated in c.5808A>T; p. (Leu1936Phe) in exon 39, and a known ATM mutation was in c.5948A>G; p. (Asn1983Ser). These novel mutations had not been reported in previous database. Subsequently, the quality statistics of these variants, including allele coverage, allele ratio, P-value, Phred quality score, sequencing coverage, PolyPhen score and alleles frequency was performed. For all variants, P-value was highly significant and the Phred quality score was high. In addition, the results from sequencing coverage demonstrated that 97.02% reads were on target and that 97.88% amplicons had at least 500 reads. These findings may serve at determining new strategies to distinguish the types of choroid plexus tumor, and at developing novel targeted therapies. Development of NGS technologies in the Kingdom of Saudi Arabia may be used in molecular pathology laboratories.
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http://dx.doi.org/10.3892/ol.2019.10882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781611PMC
November 2019

Effects of mineral trioxide aggregate, calcium hydroxide, biodentine and Emdogain on osteogenesis, Odontogenesis, angiogenesis and cell viability of dental pulp stem cells.

BMC Oral Health 2019 07 2;19(1):133. Epub 2019 Jul 2.

Department of Basic and Clinical Oral Sciences, Faculty of Dentistry, Umm Al-Qura University, Makkah, Kingdom of Saudi Arabia.

Background: Vital pulp therapy preserves and maintains the integrity and the health of dental pulp tissue that has been injured by trauma, caries or restorative procedures. The enhancement of cells viability and formation of reparative dentine and new blood vessels are vital determinants of the success of direct pulp capping. Therefore, the aims of this study was to evaluate and compare the in vitro osteogenic, odontogenic and angiogenic effects of mineral trioxide aggregate (MTA), calcium hydroxide [Ca(OH)], Biodentine and Emdogain on dental pulp stem cells (DPSCs) and examine the effects of the tested materials on cell viability.

Methods: DPSCs were treated with MTA, Ca(OH), Biodentine or Emdogain. Untreated cells were used as control. The cell viability was measured by MTT assay on day 3. Real-Time PCR with SYBR green was used to quantify the gene expression levels of osteogenic markers (alkaline phosphatase and osteopontin), odontogenic marker (dentin sialophosphoprotein) and angiogenic factor (vascular endothelial growth factor) on day 7 and day 14.

Results: All capping materials showed variable cytotoxicity against DPSCs (77% for Emdogain, 53% for MTA, 26% for Biodentine and 16% for Ca(OH) compared to control (P value < 0.0001). Osteopontin (OPN) and dentin sialophosphoprotein (DSPP) gene expression was increased by all four materials. However, alkaline phosphatase (ALP) was upregulated by all materials except Emdogain. Vascular endothelial growth factor (VEGF) expression was upregulated by all four tested materials except Ca(OH).

Conclusions: Our results suggest MTA, Biodentine and Emdogain exhibit similar attributes and may score better than Ca(OH). Emdogain could be a promising alternative to MTA and Biodentine in enhancing pulp repair capacity following dental pulp injury. However, further future research is required to assess the clinical outcomes and compare it with the in vitro findings.
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http://dx.doi.org/10.1186/s12903-019-0827-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604301PMC
July 2019

Whole exome sequencing detects novel variants in Saudi children diagnosed with eczema.

J Infect Public Health 2020 Jan 15;13(1):27-33. Epub 2019 Jun 15.

Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, PO Box-10219, Riyadh 11433, Saudi Arabia. Electronic address:

Background: Eczema is also known as atopic dermatitis is well-known for the skin disease globally. In Saudi Arabia, exome sequencing studies have not been documented. The purpose of this study was to scrutinize the disease causing mutations in children affected with eczema with exome sequencing in the Saudi population.

Methods: We recruited randomly three sporadic cases of children diagnosed with eczema and simultaneously, three more cases were adopted for control samples. Exome sequencing was carried out by applying a pipeline that captures all the variants of concern related to the samples by using the Ion torrent.

Results: In this study, we have documented 49 variants, among which 37 variants were confirmed through eczema children and remaining 30 variants through control children. However, from the analysis of the 6 samples, we have identified rs10192157 (1646C>T; Thr549Ile), rs2899642 (27C>G; Asn9Lys), chr1:152127950 (1625G>A; Gly542Asp) and chr1:152128041 (1534C>G; Gly512Arg) variants which are rarely linked to the disease eczema. In the rs10192157, we have documented these mutations in all three eczema children and one in the control; the rs2899642 mutation appeared in only a couple of eczema children, whereas the mutation in the chr1:152127950 regions appeared in only one eczema patient. However, the chr1:152128041 mutations appeared in only one case of eczema and also in two control children.

Conclusion: Our study revealed four mutations which had not previously been connected with eczema within the database. However, the rs10192157 and rs2899642 mutations were documented with asthma disease. The remaining mutations such as chr1:152127950 and chr1:152128041 have not been reported anywhere else. This study recommends screening these 4 mutations in eczema cases and their relevant controls to confirm the prevalence in the Saudi population. It is recommended that future studies examine the 4 mutations in detail.
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http://dx.doi.org/10.1016/j.jiph.2019.05.020DOI Listing
January 2020

Anomalous coronary artery anatomy with a single coronary ostium arising from the right coronary: a case report and literature review.

Int Med Case Rep J 2019 3;12:135-141. Epub 2019 May 3.

Department of Medical Genetics, Umm-Al-Qura University, Makkah, Saudi Arabia.

This article reports the case of a single coronary artery with origin from a single ostium in the right sinus of Valsalva (RSOV) with an anomalous course of the left coronary artery anterior to the pulmonary trunk. We present the case of an anomalous single coronary artery detected incidentally during routine coronary computed tomography (CT) angiography performed by a multislice CT method, using a 64-detector-row scanner. The CT examination revealed that the patient had a single large right coronary artery arising from the right sinus of Valsalva, dividing into the right coronary artery, left main coronary artery (LMCA), and left circumflex artery (LCX). The LMCA turned anteriorly in front of the pulmonary outflow tract, reaching the atrioventricular groove. The LCX artery passed posterior to the aorta (retro-aortic) and then between the left atrium and left ventricular outflow tract to reach its normal course on the left side. We present a rare case of single coronary artery congenital anomaly from the Makkah region of Saudi Arabia. This kind of coronary artery anomaly in the absence of stenosis could remain silent and asymptomatic.
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http://dx.doi.org/10.2147/IMCRJ.S194029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507107PMC
May 2019

Modifying inter-cistronic sequence significantly enhances IRES dependent second gene expression in bicistronic vector: Construction of optimised cassette for gene therapy of familial hypercholesterolemia.

Noncoding RNA Res 2019 Mar 22;4(1):1-14. Epub 2018 Nov 22.

Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, P.O. Box 715, Makkah, 21955, Saudi Arabia.

Internal ribosome entry site (IRES) sequences have become a valuable tool in the construction of gene transfer and therapeutic vectors for multi-cistronic gene expression from a single mRNA transcript. The optimal conditions for effective use of this sequence to construct a functional expression vector are not precisely defined but it is generally assumed that the internal ribosome entry site dependent expression of the second gene in such as cassette is less efficient than the cap-dependent expression of the first gene. Mainly tailoring inter-cistronic sequence significantly enhances IRES dependent second gene expression in bicistronic vector further in construction of optimised cassette for gene therapy of familial hypercholesterolemia. We tailored the size of the inter-cistronic spacer sequence at the 5' region of the internal ribosome entry site sequence using sequential deletions and demonstrated that the expression of the 3' gene can be significantly increased to similar levels as the cap-dependent expression of the 5' gene. Maximum expression efficiency of the downstream gene was obtained when the spacer is composed of 18-141 base pairs. In this case a single mRNA transcriptional unit containing both the first and the second Cistron was detected. Whilst constructs with spacer sequences of 216 bp or longer generate a single transcriptional unit containing only the first Cistron. This suggests that long spacers may affect transcription termination. When the spacer is 188 bp, both transcripts were produced simultaneously in most transfected cells, while a fraction of them expressed only the first but not the second gene. Expression analyses of vectors containing optimised cassettes clearly confirm that efficiency of gene transfer and biological activity of the expressed transgenic proteins in the transduced cells can be achieved. Furthermore, Computational analysis was carried out by molecular dynamics (MD) simulation to determine the most emerges as viable containing specific binding site and bridging of 5' and 3' ends involving direct RNA-RNA contacts and RNA-protein interactions. These results provide a mechanistic basis for translation stimulation and RNA resembling for the synergistic stimulation of cap-dependent translation.
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http://dx.doi.org/10.1016/j.ncrna.2018.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404380PMC
March 2019

Identification of six novel factor viii gene variants using next generation sequencing and molecular dynamics simulation.

Acta Biochim Pol 2019 Feb;66(1):23-31

1Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia; 2Science and Technology Unit, Umm Al Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia.

Hemophilia A is an X-linked recessive hemorrhagic disorder caused by variants in the F8 gene. To identify known and novel causative variants in hemophilia A, we have carried out genetic analysis among Saudi patients. Twenty-one patients, who were negative for inv-1/inv-22, were selected for analysis by next generation sequencing, thereafter confirmed by Sanger sequencing. In addition, the functionality and structural changes in the variant proteins were assessed using Molecular dynamics (MD) simulation and compared with wild-type and native proteins. In the samples we analyzed, we found 10 variants in 12 individuals; among them, five were novel and five were previously reported. The novel variants were located at positions: c.6130_6131insC, c.5815G>C, c.5493C>G, c.3734_3740delinsATTTCT and c.3744A>T. With the exception of one variant which was silent, the MD simulation revealed that the observed variants were causing severe structural changes when compared to the native protein and resulted in a loss of the protein's function. The MD analysis is in line with clinical data of patients who had <1% Factor VIII levels (severe hemophilia) with episodic bleeding, and were on more than one treatment. Moreover, some patients presented with chronic joint disability. These results will enrich the spectrum of variants and enlarge the factor VIII protein's database in the Saudi Arabian population.
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http://dx.doi.org/10.18388/abp.2018_2339DOI Listing
February 2019

A genetic variant c.553G > T (rs2075291) in the apolipoprotein A5 gene is associated with altered triglycerides levels in coronary artery disease (CAD) patients with lipid lowering drug.

BMC Cardiovasc Disord 2019 01 3;19(1). Epub 2019 Jan 3.

Division of Human Genetics and Genome Research, Department of Molecular Genetics and human Enzymology, National Research Centre, 33Bohouth St. Dokki, Giza, Egypt.

Background: Elevated plasma triglycerides (TGs) are widely used as a major cardiovascular risk predictor and are thought to play an important role in the progression of coronary heart disease (CHD). It has been demonstrated that lipid lowering was associated with lower mortality in patients with CHD. The present study therefore aimed to investigate the consequences of the genetic variant c.553G > T (rs2075291) in apolipoprotein A5 gene to determination of triglycerides levels in CAD patients receiving, atorvastatin, lipid lowering drug.

Methods: We here report that a recently identified genetic variant, c.553G > T in the APOA5 gene which causes a substitution of a cysteine for a glycine residue at amino acid residue 185(G185C) is also associated with increased TG levels. To investigate theses effects, a case-control study compressing 608 subjects from the same area was performed.

Results: TG levels in T allele patients were significantly lower than the control GT allele patient (χ = 2.382E2, P-value < 0.001). Overall, patients carrying T allele showed lower levels of TG than patients carrying GG allele. The homozygous patient for the T allele presented normal cholesterol levels of 134 mg/dl, and the levels in GG patients ranged from 25 to 340 mg/dl (P-value < 0.001). In summary, we demonstrated that the presence of c.553G > T variant (rs2075291); in APOA5 gene increases human plasma TG levels.

Conclusion: Nevertheless, T allele is found to reduce TG levels in CAD patients who are on the cholesterol medication, atorvastatin. Thus, c.553G > T variant can be considered as a significant predicator of hypertriglyceridemia. In addition, it could be used as a hallmark for the diagnosis and prognosis of CAD.
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http://dx.doi.org/10.1186/s12872-018-0965-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318928PMC
January 2019

Novel combined variants of LDLR and LDLRAP1 genes causing severe familial hypercholesterolemia.

Atherosclerosis 2018 10;277:425-433

Cardiovascular Prevention Unit, Department of Adult Cardiology, Prince Sultan Cardiac Centre, Riyadh, Saudi Arabia.

Background And Aims: Familial hypercholesterolemia (FH) is a predominantly autosomal dominant hereditary disorder with significant potential for expansion of coronary artery disease.

Methods: To identify candidate variant/s in FH phenotype implicated genes, next-generation sequencing was performed using a targeted customized gene panel.

Results: We recognized a 45-year-old Saudi female FH patient with double variants in the LDLR [c.1255 T > G, p.(Y419D)] and LDLRAP1 genes [c.604_605delTCinsA, p.(S202Tfs*2)]. The proband was found to be homozygous for the LDLR variant and heterozygous for the LDLRAP1 variant. Three of the proband's children were found to be double heterozygous for the LDLR/LDLRAP1 gene variant. While her other three children were heterozygous for the same single LDLR variant. Both variants were not previously reported. The variants segregation pattern correlated with the clinical picture and with the patient's lipid profile. FH severity was greater in the proband while her children did not show any clinical manifestations. The missense variant p.(Y419D) was found to be deleterious and clinically significant based on prediction identified by PolyPhen-2 and Proven. Molecular dynamics simulation was used to further analyze the effect of the variant p.(Y419D) on the structure and function of the LDLR protein. The secondary structure was investigated, as well as the solvent accessibility and stabilizing residues. The frameshift variant of the LDLRAP1 gene results in a truncated peptide that could affect the cellular internalization of LDLR/LDL complex.

Conclusions: The finding of the combined variants in LDLR/LDLRAP1 genes triggering a severe FH phenotype is essential to elaborate the spectrum of variants causing FH and to understand the genotype-phenotype correlation.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.06.878DOI Listing
October 2018

Pattern of Thyroid Lesions in Western Region of Saudi Arabia: A Retrospective Analysis and Literature Review.

J Clin Med Res 2018 Feb 30;10(2):106-116. Epub 2017 Dec 30.

Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia.

Background: Ultrasonography (US) is being recognized as a traditional way of the diagnosis of various thyroid disorders, and this will help in detecting the thyroid tumors in early stage. Thyroid nodules are common and usually benign; steps to diagnose malignancy should include a careful clinical evaluation, laboratory tests, a thyroid US exam and a fine-needle aspiration (FNA) biopsy.

Methods: A total of 173 registered cases were used for analysis in this study. Diagnosis was made following US-guided FNA cytology (FNAC) and histopathological diagnosis; clinicopathological and demographic data of all such patients were obtained and analyzed for the present study. For statistical analysis, Statistical Package of Social Sciences v.22 (SPSS) was used.

Results: In the current study, 87.3% of patients were female, and 12.7% were male. The mean age of the patients was 43.35 years, 86.4% were Saudi nationals and there was no significant difference between age groups. Overall, the distribution of lesions in all age groups was 41.6% in the right lobe, 9.3% lesions were adenomatous, 71.1% were colloid, and 10.4% were lymphocytic. The final diagnosis of thyroid lesions was confirmed after histopathological examinations. Out of 173 cases, 12.6% (20 cases) of male patients and 87.4% (139 cases) of female patients had benign lesions, respectively. Only one male case was malignant, and seven cases were malignant in female group. Eighty percent of males and 77.7% females have colloid nodules, and 15% of males and 9.3% of females have adenomatous nodules. Four cases were non-diagnostic, one case was atypia in females, and one case was suspicious of malignancy in a male.

Conclusions: Most thyroid lesions in this study population were benign, while papillary carcinoma was the most common malignancy encountered. There was a marked female predominance in all types of thyroid diseases. The most common age group affected is 30 - 39 years. In Saudi Arabia, growing prevalence of thyroid cancer may be due to the increased screening using sensitive imaging in clinical practice, and ultrasonography is the most accurate and cost-effective method for detecting thyroid lesions.
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http://dx.doi.org/10.14740/jocmr3202wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755649PMC
February 2018

Molecular Analysis of Factor VIII and Factor IX Genes in Hemophilia Patients: Identification of Novel Mutations and Molecular Dynamics Studies.

J Clin Med Res 2017 Apr 21;9(4):317-331. Epub 2017 Feb 21.

Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia.

Background: Hemophilias A and B are X-linked bleeding disorders caused by mutations in the factor VIII and factor IX genes, respectively. Our objective was to identify the spectrum of mutations of the factor VIII and factor IX genes in Saudi Arabian population and determine the genotype and phenotype correlations by molecular dynamics (MD) simulation.

Methods: For genotyping, blood samples from Saudi Arabian patients were collected, and the genomic DNA was amplified, and then sequenced by Sanger method. For molecular simulations, we have used softwares such as CHARMM (Chemistry at Harvard Macromolecular Mechanics; http://www.charmm-gui.org) and GROMACS. In addition, the secondary structure was determined based on the solvent accessibility for the confirmation of the protein stability at the site of mutation.

Results: Six mutations (three novel and three known) were identified in factor VIII gene, and six mutations (one novel and five known) were identified in factor IX gene. The factor VIII novel mutations identified were c.99G>T, p. (W33C) in exon 1, c.2138 DelA, p. (N713Tfs*9) in eon14, also a novel mutation at splicing acceptor site of exon 23 c.6430 - 1G>A. In factor IX, we found a novel mutation c.855G>C, p. (E285D) in exon 8. These novel mutations were not reported in any factor VIII or factor IX databases previously. The deleterious effects of these novel mutations were confirmed by PolyPhen2 and SIFT programs.

Conclusion: The protein functional and structural studies and the models built in this work would be appropriate for predicting the effects of deleterious amino acid substitutions causing these genetic disorders. These findings are useful for genetic counseling in the case of consanguineous marriages which is more common in the Saudi Arabia.
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http://dx.doi.org/10.14740/jocmr2876wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330775PMC
April 2017

Compound heterozygous LDLR variant in severely affected familial hypercholesterolemia patient.

Acta Biochim Pol 2017 23;64(1):75-79. Epub 2016 Nov 23.

Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.

Familial hypercholesterolemia (FH) is most commonly caused by mutations in the LDL receptor (LDLR), which is responsible for hepatic clearance of LDL from the blood circulation. We described a severely affected FH proband and their first-degree blood relatives; the proband was resistant to statin therapy and was managed on an LDL apheresis program. In order to find the causative genetic variant in this family, direct exon sequencing of the LDLR, APOB and PCSK9 genes was performed. We identified a compound heterozygous mutation in the proband with missense p.(W577C) and frameshift p.(G676Afs33) variants at exons 12 and 14 of the LDLR gene respectively. DNA sequencing of LDLR gene from the parents demonstrated that the missense variant was inherited from the mother and frameshift variant was inherited from the father. The frameshift variant resulted in a stop signal 33 codons downstream of the deletion, which most likely led to a truncated protein that lacks important functional domains, including the trans-membrane domain and the cytoplasmic tail domain. The missense variant is also predicted to be likely pathogenic and affect EGF-precursor homology domain of the LDLR protein. The segregation pattern of the variants was consistent with the lipid profile, suggesting a more severe FH phenotype when the variants are in the compound heterozygous state. The finding of a compound heterozygous mutation causing severe FH phenotype is important for the genotype-phenotype correlation and also enlarges the spectrum of FH-causative LDLR variants in the Arab population, including the Saudi population.
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http://dx.doi.org/10.18388/abp.2016_1283DOI Listing
April 2017

Functional alterations due to amino acid changes and evolutionary comparative analysis of ARPKD and ADPKD genes.

Genom Data 2016 Dec 3;10:127-134. Epub 2016 Nov 3.

King Salman Armed Forces Hospital, P.O. box 100, Tabuk, Saudi Arabia.

A targeted customized sequencing of genes implicated in autosomal recessive polycystic kidney disease (ARPKD) phenotype was performed to identify candidate variants using the Ion torrent PGM next-generation sequencing. The results identified four potential pathogenic variants in gene [c.4870C > T, p.(Arg1624Trp), c.5725C > T, p.(Arg1909Trp), c.1736C > T, p.(Thr579Met) and c.10628T > G, p.(Leu3543Trp)] among 12 out of 18 samples. However, one variant c.4870C > T, p.(Arg1624Trp) was common among eight patients. Some patient samples also showed few variants in autosomal dominant polycystic kidney disease (ADPKD) disease causing genes and such as c.12433G > A, p.(Val4145Ile) and c.1445T > G, p.(Phe482Cys), respectively. All causative variants were validated by capillary sequencing and confirmed the presence of a novel homozygous variant c.10628T > G, p.(Leu3543Trp) in a male proband. We have recently published the results of these studies (Edrees et al., 2016). Here we report for the first time the effect of the common mutation p.(Arg1624Trp) found in eight samples on the protein structure and function due to the specific amino acid changes of PKHD1 protein using molecular dynamics simulations. The computational approaches provide tool predict the phenotypic effect of variant on the structure and function of the altered protein. The structural analysis with the common mutation p.(Arg1624Trp) in the native and mutant modeled protein were also studied for solvent accessibility, secondary structure and stabilizing residues to find out the stability of the protein between wild type and mutant forms. Furthermore, comparative genomics and evolutionary analyses of variants observed in , , and genes were also performed in some mammalian species including human to understand the complexity of genomes among closely related mammalian species. Taken together, the results revealed that the evolutionary comparative analyses and characterization of , , and genes among various related and unrelated mammalian species will provide important insights into their evolutionary process and understanding for further disease characterization and management.
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http://dx.doi.org/10.1016/j.gdata.2016.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5099264PMC
December 2016

Next-generation sequencing for molecular diagnosis of autosomal recessive polycystic kidney disease.

Gene 2016 Oct 9;591(1):214-226. Epub 2016 Jul 9.

Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia; Science and Technology Unit, Umm Al -Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia. Electronic address:

Autosomal recessive polycystic kidney disease (ARPKD) a rare genetic disorder, described by formation of cysts in the kidney. A targeted customized sequencing of genes implicated in ARPKD phenotype was performed to identify candidate variants using the Ion torrent PGM next-generation sequencing. The results identified likely pathogenic disease causing variants during the validation process. Four potential pathogenic variants [c.4870C>T, p.(Arg1624Trp)], [c.5725C>T, p.(Arg1909Trp)], c.1736C>T, p.(Thr579Met)] and [(c.10628T>G), p.(Leu3543Trp)] were observed in PKHD1 gene among 12 out of 18 samples. The rest of the patient samples also showed few variants in ADPKD (Autosomal Dominant Polycystic Kidney Disease) disease causing genes PKD1 and PKD2 i.e. [c.12433G>A, p.(Val4145Ile)] and [c.1445T>G, p.(Phe482Cys)], respectively. All causative variants were validated by capillary sequencing, confirming the presence of a novel homozygous variants [c.10628T>G, p.(Leu3543Trp)] found in exon 61 of a male proband. All potentially deleterious variants identified in PKHD1, PKD1, and PKD2 gene, also exhibited pathologically or clinically significance based on the computational predictions involved in predicting the impact of non-synonymous SNPs (nsSNPs) on protein function such as Sorting Intolerant From Tolerant (SIFT) and Polymorphism Phenotyping (PolyPhen2). SIFT classified 50% of our nsSNPs as "deleterious", while PolyPhen2 identified 45% of our nsSNPs as "Probably damaged" and the results from both programs were largely complementary. Taken together, these results suggest that the NGS strategies provide a fast, accurate and cost-effective molecular diagnostic tool for identifying mutations in targeted genes sequence analysis.
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http://dx.doi.org/10.1016/j.gene.2016.07.021DOI Listing
October 2016

Identification of a recurrent frameshift mutation at the LDLR exon 14 (c.2027delG, p.(G676Afs*33)) causing familial hypercholesterolemia in Saudi Arab homozygous children.

Genomics 2016 Jan 11;107(1):24-32. Epub 2015 Dec 11.

Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia; Science and Technology Unit, Umm Al-Qura University, Makkah, Saudi Arabia. Electronic address:

Familial hypercholesterolemia (FH) is an autosomal dominant disease, predominantly caused by variants in the low-density lipoprotein (LDL) receptor gene (LDLR). Herein, we describe genetic analysis of severely affected homozygous FH patients who were mostly resistant to statin therapy and were managed on an apheresis program. We identified a recurrent frameshift mutation p.(G676Afs*33) in exon 14 of the LDLR gene in 9 probands and their relatives in an apparently unrelated Saudi families. We also describe a three dimensional homology model of the LDL receptor protein (LDLR) structure and examine the consequence of the frameshift mutation p.(G676Afs*33), as this could affect the LDLR structure in a region involved in dimer formation, and protein stability. This finding of a recurrent mutation causing FH in the Saudi population could serve to develop a rapid genetic screening procedure for FH, and the 3D-structure analysis of the mutant LDLR, may provide tools to develop a mechanistic model of the LDLR function.
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http://dx.doi.org/10.1016/j.ygeno.2015.12.001DOI Listing
January 2016

A novel SNP in 3' UTR of INS gene: A case report of neonatal diabetes mellitus.

Diabetes Res Clin Pract 2015 Sep 10;109(3):e14-7. Epub 2015 Jul 10.

Division of Human Genetics & Genome Research; Department of Molecular Genetics and Enzymology, National Research Centre, 33 Bohouth St. Dokki, Giza, Egypt. Electronic address:

Neonatal diabetes mellitus (NDM) is a rare condition with a prevalence of 1 in 300,000 live births. We have found 3 known SNPs in 5'UTR and a novel SNP in 3' UTR in the INS gene. These SNPs were present in 9-month-old girl from Saudi Arabia and also present in the father and mother. The novel SNP we found is not present in 1000 Genome project or other databases. Further, the newly identified 3' UTR mutation in the INS gene may abolish the polyadenylation signal and result in severe RNA instability.
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http://dx.doi.org/10.1016/j.diabres.2015.06.002DOI Listing
September 2015

Next generation sequencing to identify novel genetic variants causative of autosomal dominant familial hypercholesterolemia associated with increased risk of coronary heart disease.

Gene 2015 Jul 1;565(1):76-84. Epub 2015 Apr 1.

Department of Pediatrics, MBC 58, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia.

Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C). It is an autosomal dominant disease, caused by variants in Ldlr, ApoB or Pcsk9, which results in high levels of LDL-cholesterol (LDL-C) leading to early coronary heart disease. Sequencing whole genome for screening variants for FH are not suitable due to high cost. Hence, in this study we performed targeted customized sequencing of FH 12 genes (Ldlr, ApoB, Pcsk9, Abca1, Apoa2, Apoc3, Apon2, Arh, Ldlrap1, Apoc2, ApoE, and Lpl) that have been implicated in the homozygous phenotype of a proband pedigree to identify candidate variants by NGS Ion torrent PGM. Only three genes (Ldlr, ApoB, and Pcsk9) were found to be highly associated with FH based on the variant rate. The results showed that seven deleterious variants in Ldlr, ApoB, and Pcsk9 genes were pathological and were clinically significant based on predictions identified by SIFT and PolyPhen. Targeted customized sequencing is an efficient technique for screening variants among targeted FH genes. Final validation of seven deleterious variants conducted by capillary resulted to only one novel variant in Ldlr gene that was found in exon 14 (c.2026delG, p. Gly676fs). The variant found in Ldlr gene was a novel heterozygous variant derived from a male in the proband.
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http://dx.doi.org/10.1016/j.gene.2015.03.064DOI Listing
July 2015

Evidence of trem2 variant associated with triple risk of Alzheimer's disease.

PLoS One 2014 24;9(3):e92648. Epub 2014 Mar 24.

Department of Basic Sciences, College of Science and Health Professions, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.

Alzheimer's disease is one of the main causes of dementia among elderly individuals and leads to the neurodegeneration of different areas of the brain, resulting in memory impairments and loss of cognitive functions. Recently, a rare variant that is associated with 3-fold higher risk of Alzheimer's disease onset has been found. The rare variant discovered is a missense mutation in the loop region of exon 2 of Trem2 (rs75932628-T, Arg47His). The aim of this study was to investigate the evidence for potential structural and functional significance of Trem2 gene variant (Arg47His) through molecular dynamics simulations. Our results showed the alteration caused due to the variant in TREM2 protein has significant effect on the ligand binding affinity as well as structural configuration. Based on molecular dynamics (MD) simulation under salvation, the results confirmed that native form of the variant (Arg47His) might be responsible for improved compactness, hence thereby improved protein folding. Protein simulation was carried out at different temperatures. At 300K, the deviation of the theoretical model of TREM2 protein increased from 2.0 Å at 10 ns. In contrast, the deviation of the Arg47His mutation was maintained at 1.2 Å until the end of the simulation (t = 10 ns), which indicated that Arg47His had reached its folded state. The mutant residue was a highly conserved region and was similar to "immunoglobulin V-set" and "immunoglobulin-like folds". Taken together, the result from this study provides a biophysical insight on how the studied variant could contribute to the genetic susceptibility to Alzheimer's disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0092648PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3963925PMC
January 2015

DNA mismatch repair MSH2 gene-based SNP associated with different populations.

Mol Genet Genomics 2014 Jun 22;289(3):469-87. Epub 2014 Feb 22.

Department of Medical Genetics, College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia,

We screened for the major essential single-nucleotide polymorphism (SNP) variant that might be associated with the MSH2 gene based on the data available from three types of human tissue samples [156 lymphoblastoid cell variations (LCL), 160 epidermis, 166 fat]. An association analysis confirmed that the KCNK12 SNP variant (rs748780) was highly associated (p value 9 × 10(-4)) with the MSH2 gene for all three samples. Using SNP identification, we further found that the recognized SNP was also relevant among Hapmap populations. Techniques that display specific SNPs associated with the gene of interest or nearby genes provide more reliable genetic associations than techniques that rely on data from individual SNPs. We investigated the MSH2 gene regional linkage association with the determined SNP (rs748780), KCNK12 variant (Allele T>C) in the intronic region, in HapMap3 full dataset populations, Yoruba in Ibadan, Nigeria (YRI), Utah residents with ancestry from northern Europe (CEU), Han Chinese in Beijing, China (CHB), and a population of Mexican ancestry in Los Angeles, California (MEX). A gene-based SNP association analysis analyzes the combined impact of every variant within the gene while creating referrals to linkage disequilibrium or connections between markers. Our results indicated that among the four populations studied, this association was highest in the MEX population based on the r(2) value; a similar pattern was also observed in the other three populations. The relevant SNP rs748780 in KCNK12 is related to a superfamily of potassium channel pore-forming P-domain proteins as well as to other non-pore-forming proteins and has been shown to be relevant to neurological disorder predisposition in MEX as well as in other populations.
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http://dx.doi.org/10.1007/s00438-014-0826-4DOI Listing
June 2014

Identification of a novel nonsense variant c.1332dup, p.(D445*) in the LDLR gene that causes familial hypercholesterolemia.

Hum Genome Var 2014 20;1:14021. Epub 2014 Nov 20.

Department of Pediatrics, King Faisal Specialist Hospital and Research Centre , Riyadh, Saudi Arabia.

Familial hypercholesterolemia (FH) is an autosomal dominant disease predominantly caused by a mutation in the low-density lipoprotein receptor (LDLR) gene. Here, we describe two severely affected FH patients who were resistant to statin therapy and were managed on an apheresis program. We identified a novel duplication variant c.1332dup, p.(D445*) at exon 9 and a known silent variant c.1413A>G, p.(=), rs5930, NM_001195798.1 at exon 10 of the LDLR gene in both patients.
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http://dx.doi.org/10.1038/hgv.2014.21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785512PMC
April 2016

mda-7/IL-24, novel anticancer cytokine: focus on bystander antitumor, radiosensitization and antiangiogenic properties and overview of the phase I clinical experience (Review).

Int J Oncol 2007 Nov;31(5):985-1007

Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY 10032, USA.

Subtraction hybridization applied to a 'differentiation therapy' model of cancer employing human melanoma cells resulted in the cloning of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24). Initial studies confirm an inverse correlation between mda-7 expression and melanoma development and progression. Forced expression of mda-7 by means of a plasmid or via a replication incompetent adenovirus (Ad.mda-7) promotes growth suppression and induces apoptosis in a broad array of human cancers. In contrast, mda-7 does not induce growth suppressive or toxic effects in normal cells. Based on structure (containing an IL-10 signature motif), secretion by cells (including subsets of T-cells) and location on chromosome 1q (in an area containing IL-10-family genes), mda-7 has now been renamed mda-7/IL-24. Studies by several laboratories have uncovered many of mda-7/IL-24's unique properties, including cancer-specific apoptosis-induction, cell cycle regulation, an ability to inhibit angiogenesis, potent 'bystander antitumor activity' and a capacity to enhance the sensitivity of tumor cells to radiation, chemotherapy and monoclonal antibody therapy. Moreover, based on its profound cancer tropism, substantiated by in vivo human xenograft studies in nude mice, mda-7/IL-24 (administered as Ad.mda-7) was evaluated in a phase I clinical trial in patients with melanomas and solid cancers. These studies document that mda-7/IL-24 is well tolerated and demonstrates evidence of significant clinical activity. In these contexts, mda-7/IL-24 represents a unique cytokine gene with potential for therapy of human cancers. The present review focuses on three unique properties of mda-7/IL-24, namely its potent 'bystander antitumor activity', ability to sensitize tumor cells to radiation, and its antiangiogenesis properties. Additionally, an overview of the phase I clinical trial is provided. These studies affirm that mda-7/IL-24 has promise for the management of diverse cancers.
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November 2007