Publications by authors named "Saeed Talebi"

41 Publications

RNA Sequencing of CD4 T Cells in Relapsing-Remitting Multiple Sclerosis Patients at Relapse: Deciphering the Involvement of Novel genes and Pathways.

J Mol Neurosci 2021 Jul 21. Epub 2021 Jul 21.

Immunology Department, School of Medicine, Tehran University of Medical Sciences, Poorsina St, 16 Azar St., Enghelab Ave, Tehran, Iran.

CD4 T cells are known as a noteworthy potential modulator of inflammation in multiple sclerosis (MS). In the current study, we investigated the transcriptome profile of CD4 T cells in patients with relapsing-remitting MS (RRMS) at the relapse phase. We performed RNA sequencing of CD4 T cells isolated from four relapsing-remitting MS (RRMS) patients at the relapse phase and four age- and sex-matched healthy controls. The edgeR statistical method was employed to determine differentially expressed genes (DEGs). Gene set enrichment analysis was subsequently performed. Applying a physical interaction network, genes with higher degrees were selected as hub genes. A total of 1278 and 1034 genes were defined at significantly higher or lower levels, respectively, in CD4 T cells of RRMS patients at the relapse phase as compared with healthy controls. The top up- and downregulated genes were JAML and KDM3A. The detected DEGs were remarkable on chromosomes 1 and 2, respectively. The DEGs were mainly enriched in the pathways "regulation of transcription, DNA-templated," "regulation of B cell receptor signaling pathway," "protein phosphorylation," "epidermal growth factor receptor signaling pathway," and "positive regulation of neurogenesis." Moreover, 16 KEGG pathways mostly associated with the immune system and viral infections were enriched. In the constructed physical interaction networks, UBA52 and TP53 were shown to be the most highly ranked hub genes among upregulated and downregulated genes, respectively. By applying global transcriptome profiling of CD4 T cells, we deciphered the involvement of several novel genes and pathways in MS pathogenesis. The present results must be confirmed by in vivo and in vitro studies.
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http://dx.doi.org/10.1007/s12031-021-01878-8DOI Listing
July 2021

Exome sequencing reveals novel rare variants in Iranian familial multiple sclerosis: The importance of POLD2 in the disease pathogenesis.

Genomics 2021 Jul 8;113(4):2645-2655. Epub 2021 Jun 8.

Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

The prevalence of familial multiple sclerosis (FMS) is increasing worldwide which endorses the heritability of the disease. Given that many genome variations are ethnicity-specific and consanguineous marriage could affect genetic diseases, hereditary disease gene analysis among FMS patients from Iran, a country with high rates of parental consanguinity, could be highly effective in finding mutations underlying disease pathogenesis. To examine rare genetic mutations, we selected three Iranian FMS cases with ≥3 MS patients in more than one generation and performed whole exome sequencing. We identified a homozygous rare missense variant in POLD2 (p. Arg141Cys; rs372336011). Molecular dynamics analysis showed reduced polar dehydration energy and conformational changes in POLD2 mutant. Further, we found a heterozygote rare missense variant in NBFP1 (p. Gly487Asp; rs778806175). Our study revealed the possible role of novel rare variants in FMS. Molecular dynamic simulation provided the initial evidence of the structural changes behind POLD2 mutant.
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http://dx.doi.org/10.1016/j.ygeno.2021.06.008DOI Listing
July 2021

The importance of CDC27 in cancer: molecular pathology and clinical aspects.

Cancer Cell Int 2021 Mar 9;21(1):160. Epub 2021 Mar 9.

Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Shahid Hemmat Highway, P.O. Box: 14665-354, Tehran, 14496-14535, Iran.

Background: CDC27 is one of the core components of Anaphase Promoting complex/cyclosome. The main role of this protein is defined at cellular division to control cell cycle transitions. Here we review the molecular aspects that may affect CDC27 regulation from cell cycle and mitosis to cancer pathogenesis and prognosis.

Main Text: It has been suggested that CDC27 may play either like a tumor suppressor gene or oncogene in different neoplasms. Divergent variations in CDC27 DNA sequence and alterations in transcription of CDC27 have been detected in different solid tumors and hematological malignancies. Elevated CDC27 expression level may increase cell proliferation, invasiveness and metastasis in some malignancies. It has been proposed that CDC27 upregulation may increase stemness in cancer stem cells. On the other hand, downregulation of CDC27 may increase the cancer cell survival, decrease radiosensitivity and increase chemoresistancy. In addition, CDC27 downregulation may stimulate efferocytosis and improve tumor microenvironment.

Conclusion: CDC27 dysregulation, either increased or decreased activity, may aggravate neoplasms. CDC27 may be suggested as a prognostic biomarker in different malignancies.
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http://dx.doi.org/10.1186/s12935-021-01860-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941923PMC
March 2021

Conditioned media derived from mesenchymal stem cells induces apoptosis and decreases cell viability and proliferation in squamous carcinoma cell lines.

Gene 2021 May 4;782:145542. Epub 2021 Mar 4.

Division of Histology, Department of Basic Science, Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, P.O. Box: 1477893855, Tehran, Iran. Electronic address:

Squamous cell carcinoma (SCC) is a relatively common cancer with a low survival rate, poor prognosis and no effective treatment strategy. The use of cell-free conditioned media derived from mesenchymal stem cells (CM-MSCs) has shown promising results in treating various diseases. This study aimed to evaluate the effects of CM-MSCs on proliferation and apoptosis of CAL-27 and FaDu SCC cell lines. CM derived from human bone marrow and human amniotic membrane MSCs (BM-MSCs and AM-MSCs) was used in this investigation. MTT assay demonstrated that CM-BMMSC decreased the viability of CAL-27 and FaDu cell lines, 24, 48, and 72 h after treatment. Quantitative real-time PCR indicated that mRNA expression of PCNA as a proliferative marker, and BCL-2 as an anti-apoptotic protein, decreased in both cell lines treated with CM-BMMSC. Based on the flow cytometry results, the number of positive proliferative Ki67 cells and apoptotic Annexin-V cells decreased and increased in both cell lines treated with CM-BMMSC, respectively. However, CM-AMMSC treatment had both pro-and anti-neoplastic effects in our samples and showed considerable differences between the two cell lines. Taken together, our findings demonstrated that CM-BMMSC and, to a lesser degree, CM-AMMSC decrease cell viability and proliferation and increase cell apoptosis in SCC cell lines in a time-dependent manner. However, further studies are needed, especially to evaluate the anti-tumor potential of CM-BMMSC in vivo.
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http://dx.doi.org/10.1016/j.gene.2021.145542DOI Listing
May 2021

A novel metabolic disorder in the degradation pathway of endogenous methanol due to a mutation in the gene of alcohol dehydrogenase.

Clin Biochem 2021 Apr 2;90:66-72. Epub 2021 Feb 2.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Background: A small amount of methanol is produced endogenously in the human body but it is efficiently metabolized by alcohol dehydrogenase (ADH) and other enzymes, and the products eliminated without harm. In this study, we present a new entity of inborn error of methanol metabolism due to a mutation in the ADH1C gene coding for the γ subunit that is part of several ADH isoenzymes.

Results: This disorder was discovered in an 11.58-year-old boy. During one 9-month hospital admission, he had periods of 1-4 days during which he was comatose, and between these periods he was sometimes verbose and euphoric, and had ataxia, dysarthria. Following hemodialysis treatments, he became conscious and appeared healthy. Organ evaluations and his laboratory tests were normal. Toxicological evaluation of his blood showed a high methanol level [12.2 mg/dL (3.8 mmol/L), normal range up to 3.5 mg/dL (1.09 mmol/L) while the formaldehyde level was undetectable. The finding of liver function tests that were within normal limits, coupled with a normal eye examination and size of the liver, elevated blood methanol levels and an undetectable formaldehyde level, suggested ADH insufficiency. Adding zinc to the drug regimen 15 mg/daily dramatically reduced the patient's methanol level and alleviated the abnormal symptoms. When zinc supplementation was discontinued, the patient relapsed into a coma and hemodialysis was once again required. A homozygous mutation in ADH1C gene located at exon 3 was found, and both parents were heterozygous for this mutation.

Conclusion: Accumulation of methanol due to mutation in ADH1C gene may result in drunkenness and ataxia, and leads to coma. This condition can be successfully treated with zinc supplementation as the cofactor of ADH.
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http://dx.doi.org/10.1016/j.clinbiochem.2021.01.007DOI Listing
April 2021

Whole-Exome Sequencing Uncovers Novel Causative Variants and Additional Findings in Three Patients Affected by Glycogen Storage Disease Type VI and Fanconi-Bickel Syndrome.

Front Genet 2020 11;11:601566. Epub 2021 Jan 11.

Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Glycogen storage diseases (GSDs) are the heterogeneous group of disorders caused by mutations in at least 30 different genes. Different types of GSDs, especially liver GSDs, take overlapping symptoms and can be clinically indistinguishable. This survey evaluated the use of whole-exome sequencing (WES) for the genetic analysis of the liver GSD-suspected patients in three unrelated families. An in-house filtering pipeline was used to assess rare pathogenic variants in GSD-associated genes, autosomal recessive/mendelian disorder genes (carrier status for genetic counseling subjects), and the ACMG's list of 59 actionable genes. For the interpretation of the causative variants and the incidental/secondary findings, ACMG guidelines were applied. Additionally, we have explored PharmGKB class IA/IB pharmacogenetic variants. The segregation analysis was performed using Sanger sequencing for the novel causative variants. Bioinformatics analysis of the exome data in three individuals revealed three novel homozygous causative variants in the GSD-associated genes. The first variant, c.298_307delATGATCAACC in PYGL gene has related to HERS disease (GSD VI). Both variants of c.1043dupT and c.613-1G > C in SLC2A2 gene have been associated with Fanconi-Bickel syndrome (GSDXI). Eight pathogenic/likely pathogenic medical actionable findings in Mendelian disease genes and 10 pharmacogenetic variants with underlying drug response phenotypes have been identified. No known/expected pathogenic variants were detected in the ACMG's list of 59 actionable genes. The logical filtering steps can help in finding other medical actionable secondary/incidental findings as well as effectively identifying the causative variants in heterogeneous conditions such as GSDs. Three novel variants related to GSD genes recognized in liver GSD-suspected patients with early infantile and childhood-age onset.
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http://dx.doi.org/10.3389/fgene.2020.601566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831547PMC
January 2021

Whole exome sequencing revealed a novel homozygous variant in the DGKE catalytic domain: a case report of familial hemolytic uremic syndrome.

BMC Med Genet 2020 08 24;21(1):169. Epub 2020 Aug 24.

Department of Medical Genetics and Molecular Biology, school of medicine, Iran University of Medical Sciences, P.O.Box: 1449614525, Tehran, Iran.

Background: Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by microangiopathic hemolytic anemia caused by small vessel thrombosis, thrombocytopenia, and renal failure. The common cause of aHUS is a dysregulation in the alternative complement pathway. Mutations in none complement genes such as diacylglycerol kinase epsilon (DGKE) can also result in this syndrome.

Case Presentation: Here, we report on a 19-year-old female with the clinical diagnosis of aHUS, who has unaffected consanguineous parents and an older sibling who was deceased from aHUS when she was seven months old. We performed whole exome sequencing (WES) followed by evaluation of detected variants for functional significance, using several online prediction tools. Next, in order to confirm the detected pathogenic variant in proband and segregation analysis in her family, Sanger sequencing was done. The novel variant was analyzed in terms of its impact on the protein 3-dimensional structure by computational structural modeling. The results revealed that the proband carried a novel homozygous missense variant in DGKE located in exon 6 of the gene (NM_003647.3, c.942C > G [p.Asn314Lys]), and in silico analysis anticipated it as damaging. Protein computational study confirmed the influence of potential pathogenic variant on structural stability and protein function.

Conclusion: We suggest that some variations in the catalytic domain of DGKE like p.Asn314Lys which can cause alterations in secondary and 3-D structure of protein, might lead to aHUS.
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http://dx.doi.org/10.1186/s12881-020-01097-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446132PMC
August 2020

Whole Exome Sequencing Reveals a XPNPEP3 Novel Mutation Causing Nephronophthisis in a Pediatric Patient

Iran Biomed J 2020 11 31;24(6):405-8. Epub 2020 May 31.

Department of Medical Genetics and Molecular Biology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.

Background: Nephronophthisis (NPHP) is a progressive tubulointestinal kidney condition that demonstrates an AR inheritance pattern. Up to now, more than 20 various genes have been detected for NPHP, with NPHP1 as the first one detected. X-prolyl aminopeptidase 3 (XPNPEP3) mutation is related to NPHP-like 1 nephropathy and late onset NPHP.

Methods: The proband (index patient) had polyuria, polydipsia and chronic kidney disease and was clinically suspected of NPHP. After the collection of blood sample from proband and her parents, whole exome sequencing (WES) was performed to identify the possible variants in the proband from a consanguineous marriage. The functional importance of variants was estimated by bioinformatic analysis. In the affected proband and her parents, Sanger sequencing was conducted for variants’ confirmation and segregation analysis.

Results: Clinical and paraclinical investigations of the patient was not informative. Using WES, we could detect a novel homozygous frameshift mutation in XPNPEP3 (NM_022098.2: c.719_720insA; p. Q241Tfs*13), and by Sanger sequencing, we demonstrated an insertion in XPNPEP3.

Conclusion: The homozygous genotype of the novel p.Q241Tfs*31 variant in XPNPEP3 may cause NPHP in the early childhood age.
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http://dx.doi.org/10.29252/ibj.24.6.400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601541PMC
November 2020

Utilization of Whole Exome Sequencing in Lethal Form of Multiple Pterygium Syndrome: Identification of Mutations in Embryonal Subunit of Acetylcholine Receptor.

Int J Mol Cell Med 2019 ;8(4):258-269

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

The acetylcholine receptor (AChR) is a member of the superfamily of transmitter-gated ion channels having a critical role in controlling electrical signals between nerves and muscle cells. Disruptive mutations in genes encoding different subunits of AChR result in multiple pterygium syndrome (MPS), which can be associated with a severe prenatally lethal presentation. This study aimed to investigate the etiology of lethal MPS (LMPS) in two consanguineous families with a history of miscarriages. DNA was extracted from a tissue sample of two aborted fetuses (probands) from two different families with a history of spontaneous miscarriages. Parental peripheral blood samples were collected for confirmatory analysis and follow-up testing. Whole-exome sequencing (WES) was performed on DNA from the probands. The results were confirmed and segregated by Sanger sequencing. Moreover, protein structure evaluations were accomplished. We identified a homozygous frameshift mutation of c.753_754delCT (p.V253fs*44) and a homozygous missense mutation of c.715C>T (p.Arg239Cys) in the gene. Both aborted fetuses had pterygium, severe arthrogryposis, and fetal hydrops with cystic hygroma, being compatible with LMPS. The heterozygous state was confirmed in parents for both variants. Likewise, mutation was predicted to display the damaging effects by lowering the number of helixes and modifying the surface electrostatic potential. The present study identified rare sequence variants in the gene in aborted fetuses from consanguineous couples with recurrent miscarriage history. WES is a comprehensive and cost-effective approach to study heterogeneous diseases including MPS. Such findings can improve our knowledge of MPS databases, particularly for genetic counseling of high-risk families and preimplantation genetic diagnosis.
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http://dx.doi.org/10.22088/IJMCM.BUMS.8.4.258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305466PMC
January 2019

Genotype-phenotype correlation and description of two novel mutations in Iranian patients with glycogen storage disease 1b (GSD1b).

Orphanet J Rare Dis 2020 01 31;15(1):35. Epub 2020 Jan 31.

Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Background: Glycogen storage disease (GSD) is a rare inborn error of the synthesis or degradation of glycogen metabolism. GSD1, the most common type of GSD, is categorized into GSD1a and GSD1b which caused by the deficiency of glucose-6-phosphatase (G6PC) and glucose-6-phosphate transporter (SLC37A4), respectively. The high rates of consanguineous marriages in Iran provide a desirable context to facilitate finding the homozygous pathogenic mutations. This study designates to evaluate the clinical and genetic characteristics of patients with GSD1b to assess the possible genotype-phenotype correlation.

Results: Autozygosity mapping was performed on nineteen GSD suspected families to suggest the causative loci. The mapping was done using two panels of short tandem repeat (STR) markers linked to the corresponding genes. The patients with autozygous haplotype block for the markers flanking the genes were selected for direct sequencing. Six patients showed autozygosity in the candidate markers for SLC37A4. Three causative variants were detected. The recurrent mutation of c.1042_1043delCT (p.Leu348Valfs*53) and a novel missense mutation of c.365G > A (p.G122E) in the homozygous state were identified in the SLC37A4. In silico analysis was performed to predict the pathogenicity of the variants. A novel whole SLC37A4 gene deletion using long-range PCR and sequencing was confirmed as well. Severe and moderate neutropenia was observed in patients with frameshift and missense variants, respectively. The sibling with the whole gene deletion has shown both severe neutropenia and leukopenia.

Conclusions: The results showed that the hematological findings may have an appropriate correlation with the genotype findings. However, for a definite genotype-phenotype correlation, specifically for the clinical and biochemical phenotype, further studies with larger sample sizes are needed.
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http://dx.doi.org/10.1186/s13023-019-1266-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995048PMC
January 2020

Once in a Blue Moon, a Very Rare Coexistence of Glutaric Acidemia Type I and Mucopolysaccharidosis Type IIIB in a Patient

Iran Biomed J 2020 05 27;24(3):201-5. Epub 2019 Nov 27.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Background: Glutaric acidemia (GAI) and mucopolysaccharidosis type IIIB (MPSIIIB) are two rare genetic disorders caused by pathogenic variants in two different genes. Here, we report a coexistence of these two different rare disorders in an individual.

Methods: A four-year-old Iranian boy born to first-cousin parents suspected to have MPSIIIB and/or GAI was investigated in this study. Targeted genomic enrichment and next-generation sequencing were used to examine genes related to MPS and GA. Sanger sequencing was performed to confirm the results.

Results: Two homozygous likely pathogenic variants in α-N-acetylglucosaminidase (NAGLU) and GCDH genes were found and confirmed in the proband.

Conclusion: A combination of specific features of two different diseases in a patient has been reported here. More studies on this case and similar cases can provide more information about the effect of simultaneous pathogenic variants in different genes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275620PMC
May 2020

Melatonin regulates neuroinflammation ischemic stroke damage through interactions with microglia in reperfusion phase.

Brain Res 2019 11 21;1723:146401. Epub 2019 Aug 21.

Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran; Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran. Electronic address:

Even today, ischemic stroke is a major cause of death and disabilities because of its high incidence, limited treatments and poor understanding of the pathophysiology of ischemia/reperfusion, neuroinflammation and secondary injuries following ischemic stroke. The function of microglia as a part of the immune system of the brain following ischemic stroke can be destructive or protective. Recent surveys indicate that melatonin, a strong antioxidant agent, has receptors on microglial cells and can regulate them to protective form; yet, more findings are required for better understanding of this mechanism, particularly in the reperfusion phase. In this study, we initially aimed to evaluate the therapeutic efficacy of melatonin intra-arterially and to clarify the underlying mechanisms. After that by using an in vitro approach, we evaluated the protective effects of melatonin on microglial cells following the hypoxia condition. Our results proved that a single dose of melatonin at the beginning of reperfusion phase improved structural and behavioral outcomes. Melatonin increased NeuN and decreased GFAP, Iba1 and active caspase-3 at protein level. Furthermore, melatonin elevated BDNF, MAP2, HSPA1A and reduced VEGF at mRNA level. We also showed that melatonin receptor 1B highly expressed in microglial cells after 3 h hypoxia. Besides, melatonin increased the ratio of TREM2/iNOS as a marker of the most protective form of microglia (M2). In summary, our data suggest that melatonin has the possibility to serve as targeting microglial action for preventing secondary injury of reperfusion phase after ischemic stroke.
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http://dx.doi.org/10.1016/j.brainres.2019.146401DOI Listing
November 2019

Sodium Butyrate as a Histone Deacetylase Inhibitor Affects Toll-Like Receptor 4 Expression in Colorectal Cancer Cell Lines.

Immunol Invest 2019 Oct 23;48(7):759-769. Epub 2019 May 23.

Department of Medical Immunology, Faculty of Medicine, Kerman University of Medical Sciences (KMU) , Kerman , Iran.

We assessed the effect of sodium butyrate (SB) as a histone deacetylase inhibitor (HDACi) on Toll-like receptor 4 () gene expression levels, in low expressing (HCT116) and high expressing (SW480) colorectal cancer cells. The cytotoxic effect of SB was assessed by culturing SW480 and HCT116 cell lines using a broad spectrum of times and concentrations of SB. The MTT assay was done to check the cytotoxic properties of different SB concentrations. Gene expression levels of was then evaluated for non-cytotoxic SB concentrations. Morphological analysis and MTT assay confirmed that SB concentrations equal to or less than 5mM were not cytotoxic for both cell lines. At 5mM concentration of SB in SW480 cell line and 1mM concentration of SB in HCT116 cell line, gene expression level significantly increased from 24 to 48 hrs and decreased significantly from 48 to 72 hrs with an "early increased and late decreased pattern". At 1mM concentration of SB in SW480 cell line and 5mM concentration of SB in HCT116 cell line, expression had a "gradually increased pattern". This study focuses on the dose-time-effect of SB in the pathogenesis of colorectal cancer. SB alters the expression level of in colorectal cancer cells. This effect may depend on the cell type, treatment duration and SB concentration. The alterations in expression may be due to the direct effect of SB on and/or the expression changes of in other genes which may indirectly affect the expression. : TLR4: Toll-like receptor 4; HDACi: histone deacetylase inhibitor; SB: sodium Butyrate; CRC: colorectal cancer; SCFA: short-chain fatty acid; hrs: hours.
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http://dx.doi.org/10.1080/08820139.2019.1595643DOI Listing
October 2019

Multi affected pedigree with congenital microcephaly: WES revealed PNKP gene mutation.

Brain Dev 2019 Feb 5;41(2):182-186. Epub 2018 Sep 5.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Pishgam Biotech Company, Tehran, Iran. Electronic address:

Microcephaly is a rare neurological disorder, occurs in both isolated and syndromic forms. This classification could be confusing in rare disorders with variable phenotypic characteristics. However, identification of the causative gene through genetic study would allow determining the definite diagnosis. Here we reported a novel missense variant c.1133A>C (p.Lys378Thr) on the 13th exon of PNKP gene identified by whole exome sequencing (WES) in an Iranian multi-affected family with microcephaly, seizures and developmental delay (MCSZ) disorder. Data analysis suggested this variant as a pathogenic mutation which is co-segregate with the disease in the pedigree. PNKP gene mutation is consistent with the clinical features of the affected family members. Regarding both genetic findings and clinical examinations, the reported pedigree can be considered as another affected family with MCSZ syndrome, which has been reported about 10 cases worldwide. This study proves the application of WES for determining the final diagnosis in complicated neurodevelopmental disorders.
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http://dx.doi.org/10.1016/j.braindev.2018.08.005DOI Listing
February 2019

A Novel Variant in the Gene Causing Phenylketonuria in an Iranian Pedigree.

Avicenna J Med Biotechnol 2017 Jul-Sep;9(3):146-149

Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Background: gene is the well-known causative gene for classic Phenylketonuria (PKU) (OMIM#261600) disease, with more than 500 reported mutations. Through this study, a novel mutation in the gene in an Iranian pedigree with phenylketonuria was introduced.

Methods: A consanguineous family with a 10-year old affected girl was referred for genetic analysis. Mutation screening of all exons and exon-intron boundaries was performed by Sanger sequencing, and mini haplotype analysis was carried out by genotyping of Short Tandem Repeat (STR) and Variable Number Tandem Repeat (VNTR) alleles.

Results: Mutation analysis revealed a novel homozygous insertion of a single adenine nucleotide at position 335 in exon 3 of the gene. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, the change is interpreted as a pathogenic mutation which produces a premature termination signal (TAA) at codon 113 according to in silico assessments. The mini haplotype analysis showed that this mutation was linked to STR (15) -VNTR (3).

Conclusion: In this study, a novel mutation was reported in a patient who had PKU symptoms without any previously reported mutations in the gene (NM_000277.1:p.Asp112Glufs*2) that can be responsible for the classical PKU phenotype in the Iranian population. Detection of novel mutations indicates notable allelic heterogeneity of the PAH locus among this population.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501143PMC
July 2017

Genetic study of the PAH locus in the Iranian population: familial gene mutations and minihaplotypes.

Metab Brain Dis 2017 10 4;32(5):1685-1691. Epub 2017 Jul 4.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Phenylketonuria (PKU), one of the most common inborn errors of amino acid metabolism, is caused by mutations in the phenylalanine hydroxylase (PAH) gene (PAH). PKU has wide allelic heterogeneity, and over 600 different disease-causing mutations in PAH have been detected to date. Up to now, there have been no reports on the minihaplotype (VNTR/STR) analysis of PAH locus in the Iranian population. The aims of the present study were to determine PAH mutations and minihaplotypes in Iranian families with PAH deficiency and to investigate the correlation between them. A total of 81 Iranian families with PAH deficiency were examined using PCR-sequencing of all 13 PAH exons and their flanking intron regions to identify sequence variations. Fragment analysis of the PAH minihaplotypes was performed by capillary electrophoresis for 59 families. In our study, 33 different mutations were found accounting for 95% of the total mutant alleles. The majority of these mutations (72%) were distributed across exons 7, 11, 2 and their flanking intronic regions. Mutation c.1066-11G > A was the most common with a frequency of 20.37%. The less frequent mutations, p.Arg261Gln (8%), p.Arg243Ter (7.4%), p.Leu48Ser (7.4%), p.Lys363Asnfs*37 (6.79%), c.969 + 5G > A (6.17%), p.Pro281Leu (5.56), c.168 + 5G > C (5.56), and p.Arg261Ter (4.94) together comprised about 52% of all mutant alleles. In this study, a total of seventeen PAH gene minihaplotypes were detected, six of which associated exclusively with particular mutations. Our findings indicate a broad PAH mutation spectrum in the Iranian population, which is consistent with previous studies reporting a wide range of PAH mutations, most likely due to ethnic heterogeneity. High prevalence of c.1066-11G > A mutation linked to minihaplotype 7/250 among both Iranian and Mediterranean populations is indicative of historical and geographical links between them. Also, strong association between particular mutations and minihaplotypes could be useful for prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) in affected families.
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http://dx.doi.org/10.1007/s11011-017-0048-7DOI Listing
October 2017

Identification of a Novel Mutation in the PAH Gene in an Iranian Phenylketonuria Family: A Case Report.

Iran J Public Health 2017 Apr;46(4):560-564

Dept. of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Phenylketonuria (PKU) is an inborn error of amino acid metabolism with an autosomal recessive inheritance caused in most cases by mutations in the phenylalanine hydroxylase (PAH) gene. PKU has wide allelic heterogeneity. Here we report a novel heterozygous substitution (c.1223G>T (p.Arg408Leu)) in the PAH gene in an Iranian PKU family. The patient was 19-yr-old female with diagnosis of moderate PKU referred to Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran for genetic counseling/analysis in April 2015. We used PCR-Sequencing to identify any sequence variations in the PAH gene.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439047PMC
April 2017

Comparison of the effects of nobiletin and letrozole on the activity and expression of aromatase in the MCF-7 breast cancer cell line.

Biochem Cell Biol 2017 08 1;95(4):468-473. Epub 2017 Feb 1.

a Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran.

Nobiletin (NOB) is one of the polymethoxyflavones mainly found in citrus fruits. Aromatase or cytochrome P450 (CYP19) enzyme catalyzes the last and rate-limiting step in estrogen biosynthesis. This study was carried out to investigate the effect of NOB on the activity and expression of aromatase, and to compare this property with letrozole (LET) as aromatase inhibitor in the MCF-7 breast cancer cell line. Cell viability was assessed with 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assays. Aromatase enzyme activity based on the conversion of androgenic substrate testosterone into 17β-estradiol was determined. CYP19 gene expression was measured by quantitative real-time PCR. MTT assays demonstrated that NOB at a concentration of 100 μmol/L decreased cell viability in a time-dependent manner (P < 0.05). NOB significantly inhibited aromatase at the concentration of 0.1 μmol/L (P = 0.013), whereas other concentrations had no effect. Treatment with 10 μmol/L and 1 μmol/L of NOB for 48 h significantly increased (P = 0.001) and decreased (P = 0.02) relative aromatase expression, respectively. The combination of LET and NOB had no effect on aromatase. This study showed for the first time that NOB decreases the activity and expression of aromatase at low concentrations in MCF-7 breast cancer cells.
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http://dx.doi.org/10.1139/bcb-2016-0206DOI Listing
August 2017

Methylmalonic Acidemia Diagnosis by Laboratory Methods.

Rep Biochem Mol Biol 2016 10;5(1):1-14

Pardis Clinical and Genetic Laboratory, Mashhad, Iran; Immunobiochemistry Lab, Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Varastegan Institute for Medical Sciences, Mashhad, Iran.

Methylmalonic acidemia (MMA) is usually caused by a deficiency of the enzyme methylmalonyl-CoA mutase (MCM), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, cblC, cblF, cblD, and cblX), or deficiency of the enzyme methylmalonyl-CoA epimerase. A comprehensive diagnostic approach involves investigations of metabolites with tandem mass spectrometry, organic acid analysis with gas chromatography, enzymatic studies with fibroblast cell culture, and finally, mutation analysis. With biochemical techniques and enzymatic assay the reliable characterization of patients with isolated MMA for mutation analysis can be achieved. Reliable classification of these patients is essential for ongoing and prospective studies on treatments, outcomes, and prenatal diagnoses. This article reviews the diagnostic techniques used to characterize patients with MMA.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5214677PMC
October 2016

Co-existence of phenylketonuria either with maple syrup urine disease or Sandhoff disease in two patients from Iran: emphasizing the role of consanguinity.

J Pediatr Endocrinol Metab 2016 Oct;29(10):1215-1219

Most inborn errors of metabolism (IEMs) are inherited in an autosomal recessive manner. IEMs are one of the major concerns in Iran due to its extensive consanguineous marriages. Herein, we report two patients with two co-existent IEMs: a girl affected by classic phenylketonuria (PKU) and maple syrup urine disease (MSUD) and a male patient affected with Sandhoff disease and PKU, where Sandhoff disease was suspected due to the presence of a cherry-red spot in the eyes at 6 months which is unrelated to PKU. Sequencing of candidate genes in the first patient revealed one novel and three recurrent compound heterozygous mutations of p.Ser231Pro and p.Ala300Ser in the PAH gene and p.Glu330Lys and p.Arg170Cys mutations in the BCKDHB gene. Genetic testing results in the second patient showed previously reported homozygous mutations of p.Arg261Gln in the PAH and p.Arg533Cys mutation in the HEXB gene. Genetic testing confirmed the clinical diagnosis of both diseases in both patients. To the best of our knowledge; this is the first report of the co-existence of two distinct genetic disorders in two individuals from Iran. Co-existent different IEMs in patients complicated the clinical diagnosis and management of the diseases.
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http://dx.doi.org/10.1515/jpem-2016-0096DOI Listing
October 2016

Functional Analysis of A Novel Splicing Mutation in The Mutase Gene of Two Unrelated Pedigrees.

Cell J 2016 24;18(3):397-404. Epub 2016 Aug 24.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Objective: Methylmalonic acidura (MMA) is a rare autosomal recessive inborn error of metabolism. In this study we present a novel nucleotide change in the mutase (MUT) gene of two unrelated Iranian pedigrees and introduce the methods used for its functional analysis.

Materials And Methods: Two probands with definite diagnosis of MMA and a common novel variant in the MUT were included in a descriptive study. Bioinformatic prediction of the splicing variant was done with different prediction servers. Reverse transcriptionpolymerase chain reaction (RT-PCR) was done for splicing analysis and the products were analyzed by sequencing.

Results: The included index patients showed elevated levels of propionylcarnitine (C3). Urine organic acid analysis confirmed the diagnosis of MMA, and screening for mutations in the MUT revealed a novel C to G variation at the 3´ splice acceptor site in intron 12. In silico analysis suggested the change as a mutation in a conserved sequence. The splicing analysis showed that the C to G nucleotide change at position -3 in the acceptor splice site can lead to retention of the intron 12 sequence.

Conclusion: This is the first report of a mutation at the position -3 in the MUT intron 12 (c.2125-3C>G). The results suggest that the identified variation can be associated with the typical clinical manifestations of MMA.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011328PMC
http://dx.doi.org/10.22074/cellj.2016.4568DOI Listing
September 2016

An Efficient Trio-Based Mini-Haplotyping Method for Genetic Diagnosis of Phenylketonuria.

Cell J 2016 Jul-Sep;18(2):229-36. Epub 2016 May 30.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Objective: The phenylalanine hydroxylase (PAH) locus has high linkage disequilibrium. Haplotypes related to this locus may thus be considered sufficiently informative for genetic diagnosis and carrier screening using multi-allelic markers. In this study, we present an efficient method for haplotype analysis of PAH locus using multiplexing dyes. In addition, we explain how to resolve the dye shift challenge in multiplex short tandem repeat (STR) genotyping.

Materials And Methods: One hundred family trios were included in this descriptive study. The forward primer of a tetra-nucleotide STR and the reverse primer of a variable number tandem repeat (VNTR) were labeled with three different non-overlapping dyes 5-carboxyfluorescein (FAM), 6-carboxy-N,N,N',N'-tetramethylrhodamine (HEX) and 6-carboxy-N,N,N',N'-tetramethylrhodamine (TAMRA). The polymerase chain reaction (PCR) products from each family trio were multiplexed for capillary electrophoresis and results were analyzed using Peak Scanner software.

Results: Multiplexing trio products decreased the cost significantly. The TAMRA labeled products had a significant predictable shift (migrated at a slower electrophoretic rate) relative to the HEX and FAM labeled products. Through our methodology we achieve, the less inter-dye shift than intra-dye shift variance. Correcting the dye shift in the labeled products, according to the reference allele size, significantly decreased the inter-dye variability (P<0.001).

Conclusion: Multiplexing trio products helps to detect and resolve the dye shift accurately in each family, which otherwise would result in diagnostic error. The dye system of FAM, HEX and TAMRA is more feasible and cheaper than other dye systems.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988422PMC
http://dx.doi.org/10.22074/cellj.2016.4318DOI Listing
August 2016

Whole Exome Sequencing Reveals a BSCL2 Mutation Causing Progressive Encephalopathy with Lipodystrophy (PELD) in an Iranian Pediatric Patient.

Iran Biomed J 2016 Nov 25;20(5):295-301. Epub 2016 Jul 25.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Background: Progressive encephalopathy with or without lipodystrophy is a rare autosomal recessive childhood-onset seipin-associated neurodegenerative syndrome, leading to developmental regression of motor and cognitive skills. In this study, we introduce a patient with developmental regression and autism. The causative mutation was found by exome sequencing.

Methods: The proband showed a generalized hypertonia and regression of all developmental milestones. Based on the advantages of next-generation sequencing (NGS), whole exome sequencing (WES) was requested. The functional significance of variants was evaluated by NGS-specific prediction servers. Sanger sequencing was used for segregation analysis in the family.

Results: There was no specific sign in the clinical and paraclinical investigations of the patient to establish a conclusive clinical diagnosis. WES detected a known homozygous nonsense mutation in BSCL2 (NM_001122955.3:c. 985C>T; p.Arg329*). The variant is segregating in the pedigree with an autosomal recessive pattern.

Conclusion: Exome sequencing is a robust method for identifying the candidate gene variants in Mendelian traits.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075143PMC
http://dx.doi.org/10.22045/ibj.2016.07DOI Listing
November 2016

The effect of Setarud (IMOD(TM)) on angiogenesis in transplanted human ovarian tissue to nude mice.

Iran J Reprod Med 2015 Oct;13(10):605-14

Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.

Background: One of the promising methods in fertility preservation among women with cancer is cryopreservation of ovarian cortex but there are many drawbacks such as apoptosis and considerable reduction of follicular density in the transplanted ovary. One solution to reduce ischemic damage is enhancing angiogenesis after transplantation of ovarian cortex tissue.

Objective: The aim of this study was to investigate the effect of Setarud, on angiogenesis in transplanted human ovarian tissue.

Materials And Methods: In this case control study, twenty four nude mice were implanted subcutaneously, with human ovarian tissues, from four women. The mice were randomly divided into two groups (n=12): the experimental group was treated with Setarud, while control group received only vehicle. Each group was divided into three subgroups (n=4) based on the graft recovery days post transplantation (PT). The transplanted fragments were removed on days 2, 7, and 30 PT and the expression of Angiopoietin-1, Angiopoietin-2, and Vascular endothelial growth factor at both gene and protein levels and vascular density were studied in the grafted ovarian tissues.

Results: On the 2(nd) and 7(th) day PT, the level of Angiopoietin-1 gene expression in case group was significantly lower than that in control group, while the opposite results were obtained for Angiopoietin-2 and Vascular endothelial growth factor. These results were also confirmed at the protein level. The density of vessels in Setarud group elevated significantly on day 7 PT compared to pre-treatment state.

Conclusion: Our results showed that administration of Setarud may stimulates angiogenesis in transplanted human ovarian tissues, although further researches are needed before a clear judgment is made.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4668347PMC
October 2015

Comparable vitamin D3 metabolism in the endometrium of patients with recurrent spontaneous abortion and fertile controls.

Mol Reprod Dev 2015 May 23;82(5):356-64. Epub 2015 Apr 23.

Reproductive Immunology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.

Vitamin D exerts important roles during pregnancy, and its deficiency may be associated with several pregnancy complications, including pregnancy loss, yet no data are available for molecules involved in vitamin D metabolism in patients with unexplained recurrent spontaneous abortion. In this study, we investigated possible difference in endometrial expression of vitamin D3 receptor (VDR), 1α-hydroxylase (CYP27B1), and 24-hydroxylase (CYP24A1) in women with recurrent spontaneous abortion (n = 8) and healthy controls (n = 8). Gene expression of VDR, CYP27B1, and CYP24A1 was determined by real-time PCR, while VDR and CYP27B1 proteins were localized by immunohistochemistry and their abundance was validated by Western blot. We found that both patient and control groups expressed comparable levels of endometrial VDR, CYP27B1, and CYP24A1 transcripts. In line with the gene-expression results, CYP27B1 and different isoforms of VDR protein were present at the same abundance in the endometria of both groups. No significant alteration in VDR and CYP27B1 immunoreactivity pattern was found in the endometrium of patients compared to fertile controls, however. The results of the present study, therefore, do not support the hypothesis of differential expression of key molecules involved in vitamin D3 metabolism in the endometrium of recurrent spontaneous abortion patients and fertile controls.
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http://dx.doi.org/10.1002/mrd.22486DOI Listing
May 2015

Investigating the Effect of rs3783605 Single-nucleotide Polymorphism on the Activity of VCAM-1 Promoter in Human Umbilical Vein Endohelial Cells.

Iran J Allergy Asthma Immunol 2015 Apr;14(2):179-87

Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

The interaction between immune cells and endothelial lining of blood vessels is vital in many processes such as inflammatory and immune responses as well as cancer cell metastasis. The expression level of VCAM-1 is regulated by many factors including the promoter activity that is possibly affected by the single nucleotide polymorphisms (SNPs) present in the promoter. There are previous reports suggesting an important role for rs3783605 at -420 position in the pathogenesis of VCAM1-associated diseases. This is possibly due to the effect of this SNP on promoter activity and gene expression. Therefore, present study was designed to investigate the effect of rs3783605 on the activity of VCAM-1 gene promoter in human umbilical vein endothelial cells (HUVEC). In this study, two appropriate expression vectors containing VCAM1 promoter with different alleles of rs3783605 were constructed to express the Green Fluorescent Protein (GFP). Expression vectors were transfected into HUVECs and their EGFP expression level was assessed by the fluorescent microscopy and real-time PCR. Bright green fluorescence was seen in the HUVECs transfected by expression vector containing CMV promoter. The expression level in the cells transfected by vector containing promoter with A allele of rs3783605 was 0.14888 folds and G allele was about 0.37851 folds of cells transfected by vector having CMV promoter (p<0.001). Moreover, HUVECs transfected by G allele of rs3783605 showed about 2-fold higher transcriptional activity compared with the A allele, (p=0.049). Our findings showed that rs3783605 polymorphism may play a role in VCAM-1 gene expression. Therefore, it is likely that it may have an important role in the pathogenesis of VCAM1-associated diseases and tumor metastases.
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April 2015

Quantification of sperm specific mRNA transcripts (PRM1, PRM2, and TNP2) in teratozoospermia and normozoospermia: New correlations between mRNA content and morphology of sperm.

Mol Reprod Dev 2015 Jan 23;82(1):26-35. Epub 2014 Dec 23.

Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran; Department of Urology, Pediatric Urology and Andrology, Section Molecular Andrology, Justus Liebig University, Giessen, Germany.

Sperm mRNAs could be used as a predictor of fertilization capacity since the transcriptional profile of a gamete is critical for the production of viable human sperm. The aim of this study was to determine if PRM1, PRM2, and TNP2 transcripts in spermatozoa from normozoospermic and teratozoospermic men correlate with sperm morphology and/or assisted-reproduction outcomes. Human ejaculates were collected from 138 men referred to an infertility clinic, and were separated in two groups, teratozoospermic (n =72) and normozoospermic (n =66), based on World Health Organization criteria (2010). Chromomycin A3 and analine blue staining were used to evaluate protamination and chromatin integrity, respectively. Quantitative reverse-transcriptase PCR was performed for PRM1, PRM2, and TNP2. This analysis revealed significantly higher PRM1 and PRM2 mRNA copy numbers in normozoospermic versus teratozoospermic samples (P < 0.001). In contrast, TNP2 transcript abundance was significantly higher in teratozoospermic versus normozoospermic samples (P < 0.001) and positively correlated with sperm-head defects (P < 0.05). Sperm-tail defects negatively correlated (P < 0.05) with both PRM1 and PRM2 transcripts in normozoospermic samples. No significant differences were observed between the two groups when comparing transcript levels to the outcome of intracytoplasmic sperm injection cycles (P > 0.05), and a normal PRM1/PRM2 mRNA ratio (∼1) was observed in more than 70% of successful cycles. Thus, the quantity of PRM1, PRM2, and TNP2 transcripts and the PRM1/PRM2 mRNA ratio affect spermiogenesis, sperm morphology, and the function of mature human sperm. These mRNAs could therefore be used as biomarkers for the diagnosis of male infertility.
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http://dx.doi.org/10.1002/mrd.22440DOI Listing
January 2015

The effect of sortilin silencing on ovarian carcinoma cells.

Avicenna J Med Biotechnol 2014 Jul;6(3):169-77

Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.

Background: Our preliminary data on the protein expression of SORT1 in ovarian carcinoma tissues showed that sortilin was overexpressed in ovarian carcinoma patients and cell lines, while non-malignant ovaries expressed comparably lower amount of this protein. In spite of diverse ligands and also different putative functions of sortilin (NTR3), the function of overexpressed sortilin in ovarian carcinoma cells is an intriguing subject of inquiry. The aim of this study was, therefore, to investigate the functional role of sortilin in survival of ovarian carcinoma cell line.

Methods: Expression of sortilin was knocked down using RNAi technology in the ovarian carcinoma cell line, Caov-4. Silencing of SORT1 expression was assessed using real-time qPCR and Western blot analyses. Apoptosis induction was evaluated using flow cytometry by considering annexin-V FITC binding. [(3)H]-thymidine incorporation assay was also used to evaluate cell proliferation capacity.

Results: Real-time qPCR and Western blot analyses showed that expression of sortilin was reduced by nearly 70-80% in the siRNA transfected cells. Knocking down of sortilin expression resulted in increased apoptosis (27.5±0.48%) in siRNA-treated ovarian carcinoma cell line. Sortilin silencing led to significant inhibition of proliferation (40.1%) in siRNA-transfected Caov-4 cells as compared to mock control-transfected counterpart (p < 0.05).

Conclusion: As it was suspected from overexpression of sortilin in ovarian tumor cells, a cell survival role for sortilin can be deduced from these results. In conclusion, the potency of apoptosis induction via silencing of sortilin expression in tumor cells may introduce sortilin as a potential candidate for developing a novel targeted therapy in patients with ovarian carcinoma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147104PMC
July 2014

Investigation on estrogen receptor alpha gene polymorphisms in Iranian women with recurrent pregnancy loss.

Iran J Reprod Med 2014 Jun;12(6):395-400

Cell and Molecular Research Centre, Qazvin University of Medical Sciences, Qazvin, Iran.

Background: Recurrent pregnancy loss (RPL) is a multifactorial disorder. Environmental factors and genetics can affect pregnancy outcomes.

Objective: Conflicting data suggest an association between estrogen receptor alpha (ESR1) gene polymorphisms and RPL. In this study, such association was investigated in Iranian women with RPL.

Materials And Methods: In this case control study, blood samples were collected from 244 women with a history of three or more consecutive pregnancy losses and 104 healthy women with at least two live births. Using polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP), we studied -397C/T and -351A/G polymorphisms on ESR1 gene in case and control subjects.

Results: The genotypic frequencies of -397C/T and -351A/G polymorphisms on ESR1were not significantly different between RPL and control groups (p=0.20 and p=0.09, respectively). A significantly negative correlation was observed between -397C/T and -351A/G (r=-0.852, p<0.001) in RPL women and complete linkage disequilibrium between the investigated polymorphisms was found (D': 0.959; r-square= 0.758, p<0.001).

Conclusion: This investigation suggests that the analyzed polymorphisms on ESR1gene are not associated with an increased risk of RPL in the studied population.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4111887PMC
June 2014

The effect of homozygous deletion of the BBOX1 and Fibin genes on carnitine level and acyl carnitine profile.

BMC Med Genet 2014 Jul 1;15:75. Epub 2014 Jul 1.

Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.

Background: Carnitine is a key molecule in energy metabolism that helps transport activated fatty acids into the mitochondria. Its homeostasis is achieved through oral intake, renal reabsorption and de novo biosynthesis. Unlike dietary intake and renal reabsorption, the importance of de novo biosynthesis pathway in carnitine homeostasis remains unclear, due to lack of animal models and description of a single patient defective in this pathway.

Case Presentation: We identified by array comparative genomic hybridization a 42 months-old girl homozygote for a 221 Kb interstitial deletions at 11p14.2, that overlaps the genes encoding Fibin and butyrobetaine-gamma 2-oxoglutarate dioxygenase 1 (BBOX1), an enzyme essential for the biosynthesis of carnitine de novo. She presented microcephaly, speech delay, growth retardation and minor facial anomalies. The levels of almost all evaluated metabolites were normal. Her serum level of free carnitine was at the lower limit of the reference range, while her acylcarnitine to free carnitine ratio was normal.

Conclusions: We present an individual with a completely defective carnitine de novo biosynthesis. This condition results in mildly decreased free carnitine level, but not in clinical manifestations characteristic of carnitine deficiency disorders, suggesting that dietary carnitine intake and renal reabsorption are sufficient to carnitine homeostasis. Our results also demonstrate that haploinsufficiency of BBOX1 and/or Fibin is not associated with Primrose syndrome as previously suggested.
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http://dx.doi.org/10.1186/1471-2350-15-75DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184381PMC
July 2014
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