Publications by authors named "Majid Mojarrad"

63 Publications

PLA2G6 gene mutation and infantile neuroaxonal degeneration; report of three cases from Iran.

Iran J Basic Med Sci 2021 Sep;24(9):1190-1195

Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Objectives: Infantile neuroaxonal degeneration (INAD) is a rare subgroup of neurodegeneration with brain iron accumulation (NBIA) disorders. This progressive disorder may develop during the early years of life. Affected individuals mostly manifest developmental delay and/or psychomotor regression as well as other neurological deficits. In the present study, we discussed 3 INAD patients diagnosed before the age of 10 by using Whole-Exome Sequencing (WES).

Materials And Methods: We evaluated 3 pediatric patients with clinical phenotypes of INAD who underwent WES. Sanger sequencing was performed for co-segregation analysis of the variants in the families. An study was conducted for identification of the molecular function of the identified genetic variants in the gene.

Results: We detected three novel genetic variants in the PLA2G6 gene including a homozygous missense (NM_003560.2; c.1949T>C; p.Phe650Ser), a splicing (NM_001349864; c.1266-1G>A) and a frameshift variant (NM_003560.4; c.1547_1548dupCG; p.Gly517ArgfsTer29). Since the variants were not previously reported in literature or population databases, we performed in-silico studies for these variants and demonstrated their potential pathogenicity.

Conclusion: The current study reports novel genetic variants in the gene in the Iranian population, emphasizing the importance of high-throughput genetic testing in rare diseases.
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http://dx.doi.org/10.22038/ijbms.2021.55082.12340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751752PMC
September 2021

mutations causing congenital unilateral absence of the vas deferens (CUAVD) and congenital absence of the uterus (CAU) in a consanguineous family.

Asian J Androl 2021 Nov 5. Epub 2021 Nov 5.

The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, CAS Center for Excellence in Molecular Cell Science, University of Science and Technology of China, Collaborative Innovation Center of Genetics and Development, Hefei 230027, China.

Cystic fibrosis (CF) is one of the most common recessive genetic diseases, with a wide spectrum of phenotypes, ranging from infertility to severe pulmonary disease. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are considered the main genetic cause for CF. In this study, we recruited a consanguineous Iranian pedigree with four male patients diagnosed with congenital unilateral absence of the vas deferens (CUAVD), and one female patient diagnosed with congenital absence of the uterus (CAU). Testicular biopsy of one patient was performed, and hematoxylin and eosin (H and E) staining of testis sections displayed the presence of germ cell types ranging from spermatogonia to mature spermatids, indicating obstructive azoospermia. To explore the underlying genetic factor in this familial disorder, we therefore performed whole-exome sequencing (WES) on all available family members. WES data filtration and CFTR haplotype analysis identified compound heterozygous mutations in CFTR among four patients (two CUAVD patients carried p.H949Y and p.L997F, and one CUAVD and the female CAU patient carried p.H949Y and p.I148T). All these mutations were predicted to be deleterious by at least half of the prediction software programs and were confirmed by Sanger sequencing. Our study reported that CFTR compound heterozygous mutations in a consanguineous Iranian family cause infertility in both sexes.
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http://dx.doi.org/10.4103/aja202177DOI Listing
November 2021

Whole exome sequencing in 17 consanguineous Iranian pedigrees expands the mutational spectrum of inherited retinal dystrophies.

Sci Rep 2021 09 29;11(1):19332. Epub 2021 Sep 29.

Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.

Inherited retinal dystrophies (IRDs) constitute one of the most heterogeneous groups of Mendelian human disorders. Using autozygome-guided next-generation sequencing methods in 17 consanguineous pedigrees of Iranian descent with isolated or syndromic IRD, we identified 17 distinct genomic variants in 11 previously-reported disease genes. Consistent with a recessive inheritance pattern, as suggested by pedigrees, variants discovered in our study were exclusively bi-allelic and mostly in a homozygous state (in 15 families out of 17, or 88%). Out of the 17 variants identified, 5 (29%) were never reported before. Interestingly, two mutations (GUCY2D:c.564dup, p.Ala189ArgfsTer130 and TULP1:c.1199G > A, p.Arg400Gln) were also identified in four separate pedigrees (two pedigrees each). In addition to expanding the mutational spectrum of IRDs, our findings confirm that the traditional practice of endogamy in the Iranian population is a prime cause for the appearance of IRDs.
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http://dx.doi.org/10.1038/s41598-021-98677-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481312PMC
September 2021

Fragile X Syndrome in a Female With Homozygous Full-Mutation Alleles of the FMR1 Gene.

Cureus 2021 Jul 12;13(7):e16340. Epub 2021 Jul 12.

Medical Genetics Laboratory, Genetic Foundation of Khorasan Razavi, Mashhad, IRN.

Fragile X syndrome (FXS) has been reported as the leading cause of mental retardation (MR) that predominantly involves males compared to females. An over-expansion of CGG repeats in the 5' untranslated region of the FMR1 gene plays the primary role in this disease. In this study, we encountered a homozygote female patient affected by FMR1 expansion mutation. Surprisingly, she had inherited her full-mutated alleles from two different ancestors. This condition is an extremely rare case of FXS. After accurate genetic counseling, family members were referred to the laboratory for genetic testing. Karyotype with two X chromosomes was the finding after the G-banding study of the proband. Molecular analysis indicated that she was a female with full-mutated or pre-mutated alleles on both of her X chromosomes. It is a rare phenomenon that we detected in this patient. We have concluded that a combination of allele instability during oogenesis and inheritance of two alleles are the leading cause of MR in the presented case.
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http://dx.doi.org/10.7759/cureus.16340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357243PMC
July 2021

Identification of Balanced and Unbalanced Complex Chromosomal Rearrangement Involving Chromosomes 1, 11, and 15.

Cureus 2021 Jul 4;13(7):e16166. Epub 2021 Jul 4.

Medical Genetics Laboratory, Genetic Foundation of Khorasan Razavi, Mashhad, IRN.

Chromosomal abnormalities are the common genetic factors that significantly impact fertility, miscarriage possibility and abnormal offspring with unbalanced karyotype. Complex chromosomal rearrangements (CCRs) refer to structural rearrangements which involve more than two breakpoints and often more than two chromosomes. According to the mode of transmission, they can be either familial or rearrangements. Here we report a complex chromosomal rearrangement leading to intellectual disability, speech delay and multiple dysmorphic features, including cleft lip and inguinal hernia. Proband karyotype shows 46,XY,ins (1::11) (q42→qter::q25) compatible to partial trisomy 1 q42→qter, while the karyotype of his mother was 45,XX, ins (1::15) (q42;q11.1→qter), t (1;11)(q42,q25) compatible to apparently normal female phenotype.
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http://dx.doi.org/10.7759/cureus.16166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330808PMC
July 2021

Genetics and molecular biology of male infertility among Iranian population: an update.

Am J Transl Res 2021 15;13(6):5767-5785. Epub 2021 Jun 15.

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

Infertility is one of the main social and health problems among young couples. Although a noticeable ratio of infertilities are asymptomatic, about half of the cases are observed among males. Various environmental factors such as life style, dietary patterns, and pathogens are associated with male infertility. Mutations and chromosomal abnormalities are also the most important genetic risk factors of male infertility. Similar to other populations, there is a dramatically rising trend of male infertility among Iranian. Regarding the high ratio of asymptomatic cases, it is required to clarify the molecular biology and cellular processes involved in male infertility in this population to suggest an efficient panel of diagnostic markers. In this review, we have summarized all of the cellular and molecular processes which have been reported among Iranian infertile males to clarify the molecular biology of male infertility in this population. It was observed that the stress response, cellular detoxification, and DNA repair processes were the most common aberrant cellular mechanisms among Iranian infertile males. This review paves the way of introducing a population-based diagnostic panel of genetic markers among Iranian infertile males.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290737PMC
June 2021

TMEM263: a novel candidate gene implicated in human autosomal recessive severe lethal skeletal dysplasia.

Hum Genomics 2021 07 8;15(1):42. Epub 2021 Jul 8.

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

Introduction: Skeletal dysplasia is a common, clinically and genetically heterogeneous disorder in the human population. An increasing number of different genes are being identified causing this disorder. We used whole exome sequencing (WES) for detection of skeletal dysplasia causing mutation in a fetus affected to severe lethal skeletal dysplasia.

Patient: Fetus was assessed by ultrasonography in second trimester of pregnancy. He suffers from severe rhizomelic dysplasia and also pathologic shortening of ribs. WES was applied to finding of causal mutation. Furthermore, bioinformatics analysis was performed to predict mutation impact.

Results: Whole exome sequencing (WES) identified a homozygous frameshift mutation in the TMEM263 gene in a fetus with severe lethal skeletal dysplasia. Mutations of this gene have been previously identified in dwarf chickens, but this is the first report of involvement of this gene in human skeletal dysplasia. This gene plays a key role in the growth hormone signaling pathway.

Conclusion: TMEM263 can be considered as a new gene responsible for skeletal dysplasia. Given the complications observed in the affected fetus, the mutation of this gene appears to produce much more intense complications than that found in chickens and is likely to play a more important role in bone development in human.
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http://dx.doi.org/10.1186/s40246-021-00343-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268343PMC
July 2021

Expression and Prognostic Significance of Cancer/Testis Antigens, MAGE-E1, GAGE, and SOX-6, in Glioblastoma: An Immunohistochemistry Evaluation.

Iran J Pathol 2021 20;16(2):128-136. Epub 2020 Dec 20.

Department of Medical Genetics, Mashhad University of Medical Sciences, Mashhad, Iran.

Background & Objective: Glioblastoma is the most common primary malignancy of the brain, the prognosis of which is poor. Immunotherapy with cancer/testis (CT) antigens is a novel therapeutic approach for glioblastoma. This study aimed to investigate the expression rate of MAGE-E1, GAGE, and SOX-6 in glioblastoma tumors using the method of immunohistochemistry (IHC).

Methods: Expression of MAGE-E1, GAGE, and SOX-6 were determined by IHC in 50 paraffin blocks of glioblastoma. The results were compared between variables including age, gender, tumor location, and Karnofsky performance status (Kps) score. Survival analysis was also performed.

Results: The expression levels of SOX-6, MAGE-E1, and GAGE were 82%, 78%, and 76%, respectively. The relationship between CT antigens and age, gender, and tumor location was not significant, while the association between MAGE-E1 expression and age was statistically significant (=0.002). High expression levels of SOX-6 and MAGE-E1 were associated with low Kps scores (=0.034 and <0.001, respectively). Survival analysis showed that age >40 and Kps score <80 were associated with significant relationship with shorter survival rate. (=0.005 and =0.018, respectively). Expression of MAGE-E1 and GAGE was negatively associated with overall 2-year survival rate (=0.001 and =0.021, respectively).

Conclusion: The expression of all the three CT antigens, especially MAGE-E1 and SOX-6, was high in patients with glioblastoma. It can be concluded that these markers could be ideal targets for immunotherapy in such patients. MAGE-E1 and SOX-6 can be considered as important markers in determining the prognosis of glioblastoma.
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http://dx.doi.org/10.30699/IJP.2020.125038.2368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085292PMC
December 2020

TMEM218 dysfunction causes ciliopathies, including Joubert and Meckel syndromes.

HGG Adv 2021 Jan 21;2(1). Epub 2020 Nov 21.

Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.

The Joubert-Meckel syndrome spectrum is a continuum of recessive ciliopathy conditions caused by primary cilium dysfunction. The primary cilium is a microtubule-based, antenna-like organelle that projects from the surface of most human cell types, allowing them to respond to extracellular signals. The cilium is partitioned from the cell body by the transition zone, a known hotspot for ciliopathy-related proteins. Despite years of Joubert syndrome (JBTS) gene discovery, the genetic cause cannot be identified in up to 30% of individuals with JBTS, depending on the cohort, sequencing method, and criteria for pathogenic variants. Using exome and targeted sequencing of 655 families with JBTS, we identified three individuals from two families harboring biallelic, rare, predicted-deleterious missense variants. Via MatchMaker Exchange, we identified biallelic variants in four additional families with ciliopathy phenotypes. Of note, four of the six families carry missense variants affecting the same highly conserved amino acid position 115. Clinical features included the molar tooth sign (N = 2), occipital encephalocele (N = 5, all fetuses), retinal dystrophy (N = 4, all living individuals), polycystic kidneys (N = 2), and polydactyly (N = 2), without liver involvement. Combined with existing functional data linking TMEM218 to ciliary transition zone function, our human genetic data make a strong case for TMEM218 dysfunction as a cause of ciliopathy phenotypes including JBTS with retinal dystrophy and Meckel syndrome. Identifying all genetic causes of the Joubert-Meckel spectrum enables diagnostic testing, prognostic and recurrence risk counseling, and medical monitoring, as well as work to delineate the underlying biological mechanisms and identify targets for future therapies.
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http://dx.doi.org/10.1016/j.xhgg.2020.100016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009330PMC
January 2021

Chemokines as the critical factors during bladder cancer progression: an overview.

Int Rev Immunol 2021 16;40(5):344-358. Epub 2021 Feb 16.

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

Bladder cancer (BCa) is one of the most frequent urogenital malignancies which is mainly observed among men. There are various genetic and environmental risk factors associated with BCa progression. Transurethral endoscopic resection and open ablative surgery are the main treatment options for muscle invasive BCa. BCG therapy is also employed following the endoscopic resection to prevent tumor relapse. The tumor microenvironment is the main interaction site of tumor cells and immune system in which the immune cells are recruited via chemokines and chemokine receptors. In present review we summarized the main chemokines and chemokine receptors which have been associated with histopathological features of BCa patients in the world. This review highlights the chemokines and chemokine receptors as critical markers in early detection and therapeutic purposes among BCa patients and clarifies their molecular functions during BCa progression and metastasis.
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http://dx.doi.org/10.1080/08830185.2021.1877287DOI Listing
October 2021

Genetic and molecular biology of systemic lupus erythematosus among Iranian patients: an overview.

Auto Immun Highlights 2021 Jan 30;12(1). Epub 2021 Jan 30.

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

Background: Systemic lupus erythematosus (SLE) is a clinicopathologically heterogeneous chronic autoimmune disorder affecting different organs and tissues. It has been reported that there is an increasing rate of SLE incidence among Iranian population. Moreover, the Iranian SLE patients have more severe clinical manifestations compared with other countries. Therefore, it is required to introduce novel methods for the early detection of SLE in this population. Various environmental and genetic factors are involved in SLE progression.

Main Body: In present review we have summarized all of the reported genes which have been associated with clinicopathological features of SLE among Iranian patients.

Conclusions: Apart from the reported cytokines and chemokines, it was interestingly observed that the apoptosis related genes and non-coding RNAs were the most reported genetic abnormalities associated with SLE progression among Iranians. This review clarifies the genetics and molecular biology of SLE progression among Iranian cases. Moreover, this review paves the way of introducing an efficient panel of genetic markers for the early detection and better management of SLE in this population.
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http://dx.doi.org/10.1186/s13317-020-00144-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847600PMC
January 2021

AutoMap is a high performance homozygosity mapping tool using next-generation sequencing data.

Nat Commun 2021 01 22;12(1):518. Epub 2021 Jan 22.

Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland.

Homozygosity mapping is a powerful method for identifying mutations in patients with recessive conditions, especially in consanguineous families or isolated populations. Historically, it has been used in conjunction with genotypes from highly polymorphic markers, such as DNA microsatellites or common SNPs. Traditional software performs rather poorly with data from Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS), which are now extensively used in medical genetics. We develop AutoMap, a tool that is both web-based or downloadable, to allow performing homozygosity mapping directly on VCF (Variant Call Format) calls from WES or WGS projects. Following a training step on WES data from 26 consanguineous families and a validation procedure on a matched cohort, our method shows higher overall performances when compared with eight existing tools. Most importantly, when tested on real cases with negative molecular diagnosis from an internal set, AutoMap detects three gene-disease and multiple variant-disease associations that were previously unrecognized, projecting clear benefits for both molecular diagnosis and research activities in medical genetics.
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http://dx.doi.org/10.1038/s41467-020-20584-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822856PMC
January 2021

Non coding RNAs as the critical factors in chemo resistance of bladder tumor cells.

Diagn Pathol 2020 Nov 12;15(1):136. Epub 2020 Nov 12.

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

Background: Bladder cancer (BCa) is the ninth frequent and 13th leading cause of cancer related deaths in the world which is mainly observed among men. There is a declining mortality rates in developed countries. Although, the majority of BCa patients present Non-Muscle-Invasive Bladder Cancer (NMIBC) tumors, only 30% of patients suffer from muscle invasion and distant metastases. Radical cystoprostatectomy, radiation, and chemotherapy have proven to be efficient in metastatic tumors. However, tumor relapse is observed in a noticeable ratio of patients following the chemotherapeutic treatment. Non-coding RNAs (ncRNAs) are important factors during tumor progression and chemo resistance which can be used as diagnostic and prognostic biomarkers of BCa.

Main Body: In present review we summarized all of the lncRNAs and miRNAs associated with chemotherapeutic resistance in bladder tumor cells.

Conclusions: This review paves the way of introducing a prognostic panel of ncRNAs for the BCa patients which can be useful to select a proper drug based on the lncRNA profiles of patients to reduce the cytotoxic effects of chemotherapy in such patients.
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http://dx.doi.org/10.1186/s13000-020-01054-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659041PMC
November 2020

Whole exome sequencing and homozygosity mapping reveals genetic defects in consanguineous Iranian families with inherited retinal dystrophies.

Sci Rep 2020 11 10;10(1):19413. Epub 2020 Nov 10.

Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.

Inherited retinal dystrophies (IRDs), displaying pronounced genetic and clinical heterogeneity, comprise of a broad range of diseases characterized by progressive retinal cell death and gradual loss of vision. By the combined use of whole exome sequencing (WES), SNP-array and WES-based homozygosity mapping, as well as directed DNA sequencing (Sanger), we have identified nine pathogenic variants in six genes (ABCA4, RPE65, MERTK, USH2A, SPATA7, TULP1) in 10 consanguineous Iranian families. Six of the nine identified variants were novel, including a putative founder mutation in ABCA4 (c.3260A>G, p.Glu1087Gly), detected in two families from Northeastern Iran. Our findings provide additional information to the molecular pathology of IRDs in Iran, hopefully contributing to better genetic counselling and patient management in the respective families from this country.
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http://dx.doi.org/10.1038/s41598-020-75841-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655865PMC
November 2020

A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome.

Eur J Hum Genet 2021 02 8;29(2):271-279. Epub 2020 Sep 8.

Department of Pediatrics, Ain Shams University, Cairo, Egypt.

Trafficking protein particle (TRAPP) complexes, which include the TRAPPC4 protein, regulate membrane trafficking between lipid organelles in a process termed vesicular tethering. TRAPPC4 was recently implicated in a recessive neurodevelopmental condition in four unrelated families due to a shared c.454+3A>G splice variant. Here, we report 23 patients from 17 independent families with an early-infantile-onset neurodegenerative presentation, where we also identified the homozygous variant hg38:11:119020256 A>G (NM_016146.5:c.454+3A>G) in TRAPPC4 through exome or genome sequencing. No other clinically relevant TRAPPC4 variants were identified among any of over 10,000 patients with neurodevelopmental conditions. We found the carrier frequency of TRAPPC4 c.454+3A>G was 2.4-5.4 per 10,000 healthy individuals. Affected individuals with the homozygous TRAPPC4 c.454+3A>G variant showed profound psychomotor delay, developmental regression, early-onset epilepsy, microcephaly and progressive spastic tetraplegia. Based upon RNA sequencing, the variant resulted in partial exon 3 skipping and generation of an aberrant transcript owing to use of a downstream cryptic splice donor site, predicting a premature stop codon and nonsense mediated decay. These data confirm the pathogenicity of the TRAPPC4 c.454+3A>G variant, and refine the clinical presentation of TRAPPC4-related encephalopathy.
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http://dx.doi.org/10.1038/s41431-020-00717-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868361PMC
February 2021

Role of tyrosine kinases in bladder cancer progression: an overview.

Cell Commun Signal 2020 08 14;18(1):127. Epub 2020 Aug 14.

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

Background: Bladder cancer (BCa) is a frequent urothelial malignancy with a high ratio of morbidity and mortality. Various genetic and environmental factors are involved in BCa progression. Since, majority of BCa cases are diagnosed after macroscopic clinical symptoms, it is required to find efficient markers for the early detection. Receptor tyrosine-kinases (RTKs) and non-receptor tyrosine-kinases (nRTKs) have pivotal roles in various cellular processes such as growth, migration, differentiation, and metabolism through different signaling pathways. Tyrosine-kinase deregulations are observed during tumor progressions via mutations, amplification, and chromosomal abnormalities which introduces these factors as important candidates of anti-cancer therapies.

Main Body: For the first time in present review we have summarized all of the reported tyrosine-kinases which have been significantly associated with the clinicopathological features of BCa patients.

Conclusions: This review highlights the importance of tyrosine-kinases as critical markers in early detection and therapeutic purposes among BCa patients and clarifies the molecular biology of tyrosine-kinases during BCa progression and metastasis. Video abstract.
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http://dx.doi.org/10.1186/s12964-020-00625-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427778PMC
August 2020

The worldwide frequency of MYO15A gene mutations in patients with non-syndromic hearing loss: A meta-analysis.

Iran J Basic Med Sci 2020 Jul;23(7):841-848

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

is the third most crucial gene in hereditary sensorineural hearing loss after and . In the present study, we reviewed the prevalence of mutations in patients with autosomal recessive non-syndromic hearing loss (ARNSHL). In this meta-analysis, we conducted a search of PubMed, Web of Science, Excerpta Medica Database, and Scopus, and identified the articles up to September 2019 without any time limit. Two investigators independently selected the relevant papers and extracted the required information. A total of 44 case-control and case series studies were considered, and 4176 patients and 3706 healthy individuals, as the control group, were included. The pooled frequency of mutations between patients suffering from ARNSHL was calculated as 6.2% (95% CI: 4.9-7.8, -value<0.001). There was heterogeneity between our studies (-value<0.001, I2=58.1%); therefore, the random-effects model was utilized for analysis. Given the results, in many countries, the gene has a significant contribution to hearing loss. Moreover, in several regions, specific dominant mutations in this gene have been reported. Therefore, the ethnic background should be considered to investigate the mutations of the gene.
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http://dx.doi.org/10.22038/IJBMS.2020.35977.8563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395192PMC
July 2020

Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder.

Brain 2020 08;143(8):2437-2453

Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.

In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.
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http://dx.doi.org/10.1093/brain/awaa204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447524PMC
August 2020

Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants.

Brain 2020 08;143(8):2388-2397

UCL Queen Square Institute of Neurology, University College London, London, UK.

Gamma-aminobutyric acid (GABA) and glutamate are the most abundant amino acid neurotransmitters in the brain. GABA, an inhibitory neurotransmitter, is synthesized by glutamic acid decarboxylase (GAD). Its predominant isoform GAD67, contributes up to ∼90% of base-level GABA in the CNS, and is encoded by the GAD1 gene. Disruption of GAD1 results in an imbalance of inhibitory and excitatory neurotransmitters, and as Gad1-/- mice die neonatally of severe cleft palate, it has not been possible to determine any potential neurological dysfunction. Furthermore, little is known about the consequence of GAD1 disruption in humans. Here we present six affected individuals from six unrelated families, carrying bi-allelic GAD1 variants, presenting with developmental and epileptic encephalopathy, characterized by early-infantile onset epilepsy and hypotonia with additional variable non-CNS manifestations such as skeletal abnormalities, dysmorphic features and cleft palate. Our findings highlight an important role for GAD1 in seizure induction, neuronal and extraneuronal development, and introduce GAD1 as a new gene associated with developmental and epileptic encephalopathy.
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http://dx.doi.org/10.1093/brain/awaa178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447512PMC
August 2020

The rK39 Antigen from an Iranian Strain of : Detection of Anti- Antibodies in Humans and Dogs.

Iran J Parasitol 2020 Jan-Mar;15(1):48-56

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

Background: Visceral leishmaniasis (VL) is the most severe form of leishmaniasis in Iran with high mortality rates in the case of inaccurate diagnosis and treatment. This study aimed to prepare and evaluate a new rk39 recombinant antigen from an Iranian strain of for diagnosis of VL in humans and dogs.

Methods: rK39-based enzyme-linked immunosorbent assay (ELISA) was compared with the direct agglutination test (DAT) for the detection of anti antibodies. We screened 84 human sera and 87 dog sera from clinical cases in the endemic area of Meshkin-Shahr, Iran along with 176 sera from healthy controls (collected from 86 humans and 90 dogs) during 2013-2016.

Results: Using the rK39 ELISA, a sensitivity of 85.7% (95% CI, 95-99%) and a specificity of 86.0% (95% CI, 95%-99%) were detected in human sera at a 1:800 (cut-off) titer when DAT-confirmed cases were compared with healthy controls; a sensitivity of 96.6% (95% CI, 95%-99%) and specificity of 94.4% (95% CI, 95%-99%) were found at a 1:80 (cut-off) titer compared with DAT. Kappa analysis indicated agreement between the rK39 ELISA and DAT (0.718) when using human sera at a 1:800 (cut-off) titer as well as (0.910) at a 1:80 (cut-off) titer when using dog sera (<0.05).

Conclusion: New rk39 recombinant antigen from an Iranian strain of seems to be used for diagnosis of VL in humans and dogs. Further extended field studies are recommended.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244836PMC
June 2020

Role of extra cellular proteins in gastric cancer progression and metastasis: an update.

Genes Environ 2020 15;42:18. Epub 2020 May 15.

2Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Gastric cancer (GC) is one of the most common cancers in the world with a high ratio of mortality. Regarding the late diagnosis, there is a high ratio of distant metastasis among GC cases. Despite the recent progresses in therapeutic modalities, there is not still an efficient therapeutic method to increase survival rate of metastatic GC cases.

Main Body: Apart from the various intracellular signaling pathways which are involved in tumor cell migration and metastasis, the local microenvironment is also a critical regulator of tumor cell migration. Indeed, the intracellular signaling pathways also exert their final metastatic roles through regulation of extra cellular matrix (ECM). Therefore, it is required to assess the role of extra cellular components in biology of GC.

Conclusion: In the present review, we summarize 48 of the significant ECM components including 17 ECM modifying enzymes, seven extracellular angiogenic factors, 13 cell adhesion and cytoskeletal organizers, seven matricellular proteins and growth factors, and four proteoglycans and extra cellular glycoproteins. This review paves the way of determination of a specific extra cellular diagnostic and prognostic panel marker for the GC patients.
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http://dx.doi.org/10.1186/s41021-020-00157-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227337PMC
May 2020

NR1H4-related Progressive Familial Intrahepatic Cholestasis 5: Further Evidence for Rapidly Progressive Liver Failure.

J Pediatr Gastroenterol Nutr 2020 06;70(6):e111-e113

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX.

Pathogenic sequence variants in the nuclear bile acid receptor FXR, encoded by NR1H4, have been reported in a small number of children with low-γ-glutamyl transferase (GGT) cholestasis progressing to liver failure. We describe 3 additional children from 2 unrelated families with cholestasis and liver failure because of pathologic variants in NR1H4. One patient underwent liver transplantation and has had good clinical outcomes in 6 years of follow-up. Although that patient has biochemical evidence of increased bile acid synthetic activity, he has not experienced post-transplant diarrhea or allograft steatosis, as has been reported among other transplanted patients.
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http://dx.doi.org/10.1097/MPG.0000000000002670DOI Listing
June 2020

Genetics of blood malignancies among Iranian population: an overview.

Diagn Pathol 2020 May 6;15(1):44. Epub 2020 May 6.

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

Background: Blood malignancies are among the leading causes of cancer related deaths in the world. Different environmental and genetic risk factors are involved in progression of blood malignancies. It has been shown that the lifestyle changes have affected the epidemiological patterns of these malignancies. Hematologic cancers are the 5th common cancer among Iranian population. It has been observed that there is a rising trend of blood malignancies incidences during the recent decades. Therefore, it is required to design novel diagnostic methods for the early detection of such malignancies in this population.

Main Body: In present review we have summarized all of the significant genes which have been reported among Iranian patients with blood malignancies. The reported genes were categorized based on their cell and molecular functions to clarify the molecular biology and genetics of blood malignancies among Iranian patients.

Conclusion: It was observed that the epigenetic and immune response factors were the most frequent molecular processes associated with progression of blood malignancies among Iranian population. This review paves the way of introducing a population based panel of genetic markers for the early detection of blood malignancies in this population.
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http://dx.doi.org/10.1186/s13000-020-00968-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201799PMC
May 2020

Genetic and molecular biology of bladder cancer among Iranian patients.

Mol Genet Genomic Med 2020 06 6;8(6):e1233. Epub 2020 Apr 6.

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

Background: Bladder cancer (BC) is the sixth common cancer among Iranians. Various risk factors such as smoking, body mass index, chronic infection, age, and genetic factors are associated with BC progression.

Methods: It has been shown that a significant ratio of patients have tumors with muscle bladder layer invasion and poor prognosis at the time of diagnosis. Therefore, the early detection of tumors is required to reduce the mortality rate of BC cases. Since there is a wide geographical incidence variation in BC in Iran, it seems that the ethnic and genetic factors can be the main risk factors among Iranian BC patients.

Results: For the first time, in present review we have summarized all of the reported genes among Iranian BC patients until now which were significantly associated with tumorigenesis. Moreover, we categorized all of the reported genes based on their cell and molecular functions to clarify the genetic and molecular biology of BC among Iranian population.

Conclusion: This review paves the way of determination of a population-based genetic panel markers for the early detection of BC in this population.
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http://dx.doi.org/10.1002/mgg3.1233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284045PMC
June 2020

Common therapeutic advances for Duchenne muscular dystrophy (DMD).

Int J Neurosci 2021 Apr 3;131(4):370-389. Epub 2020 Apr 3.

Medical Genetics Research Center, Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Duchenne muscular dystrophy (DMD), a lethal X-linked recessive muscle dystrophy, is resulted in by different mutations including mostly frame-shifting gross deletions and duplications and rarely point mutations in DMD gene. Increasing weakness, progressive loss of skeletal muscle mass, and later-onset cardiomyopathy are serious clinical symptoms which ultimately lead to cardiac and respiratory failure, and premature death in DMD patients by age of 30. DMD is a prevalent genetic disorder and considers as an interesting target for gene therapy approaches. Massive gene size and existence of enormous number of muscle tissues are terrific hindrance against DMD treatments, nevertheless enormous efforts have been executed in the fields of gene replacement therapy, gene editing strategies, cell-based treatments, and small drug medications. Hot spot exons skipping and suppression of premature stop codons are the most interesting treatments for restoring functional DMD product, dystrophin protein. Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas) systems are the most interesting genome editing platforms that are able to restore open reading frame of DMD gene. CRISPR-Cas9 and CRISPR-Cpf1 are two main genome editing sub-types that successfully used in mice. This review aims to present recent progresses and future prospects over three main DMD therapeutic subgroups including gene therapy, cell therapy, and pharmacological therapy.
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http://dx.doi.org/10.1080/00207454.2020.1740218DOI Listing
April 2021

Investigation of MYO15A and MYO7A Mutations in Iranian Patients with Nonsyndromic Hearing Loss.

Fetal Pediatr Pathol 2021 Apr 30;40(2):121-130. Epub 2020 Jan 30.

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

Background: Hearing loss (HL) is the most common sensory disorder in humans, which affects individuals in both inherited and acquired forms. MYO15A and MYO7A gene mutations have a significant role in the development of deafness. In this study, we assessed the prevalence of MYO15A and MYO7A mutations in one hundred non-relative deaf Iranians. The existence of MYO15A and MYO7A mutations were assessed using the tetra-primer ARMS-PCR method, High Resolution Melting (HRM) and sequencing method. A heterozygote missense mutation, p.V2135L (c.6403G > T) in the MYO15A gene, was found in a patient using the sequencing method. These results explain the negligible prevalence of selected mutations among Iranian patients. Identifying common mutations in patients of an ethnic group can reduce the financial costs and time needed for identifying the causes of deafness.
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http://dx.doi.org/10.1080/15513815.2019.1686790DOI Listing
April 2021

Long non-coding RNAs as the critical factors during tumor progressions among Iranian population: an overview.

Cell Biosci 2020 14;10. Epub 2020 Jan 14.

2Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Cancer is associated with various genetic and environmental risk factors. Beside the mutations or aberrant expression of protein-coding genes, the genetic deregulation of non-coding RNAs has also an important role during tumor progression and metastasis. Long non-coding RNAs (lncRNAs) are a class of ncRNAs larger than 200 nucleotides that may function as tumor-suppressor or oncogene.

Main Body: There is a raising trend of cancer incidence among Iranian population during the last decades. Therefore, it is required to prepare a general population specific panel of genetic markers for the early detection of cancer in this population. The tissue-specific expression characteristics and high stability in body fluids highlight the lncRNAs as efficient diagnostic and prognostic noninvasive biomarkers in cancer. In present review we summarized all of the lncRNAs which have been reported until now in different tumors among Iranian patients.

Conclusions: This review paves the way of introducing a population based noninvasive diagnostic panel of lncRNAs for the early detection of tumor cells among Iranian population.
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http://dx.doi.org/10.1186/s13578-020-0373-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961246PMC
January 2020

Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases.

Acta Neuropathol 2020 03 9;139(3):415-442. Epub 2019 Dec 9.

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

Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies.
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http://dx.doi.org/10.1007/s00401-019-02109-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035241PMC
March 2020

An Overview of the CRISPR-Based Genomic- and Epigenome-Editing System: Function, Applications, and Challenges.

Adv Biomed Res 2019 21;8:49. Epub 2019 Aug 21.

Department of Medical Genetics, Mashhad University of Medical Sciences, Mashhad, Iran.

Developing a new strategy for an efficient targeted genome editing has always been a great perspective in biology. Although different approaches have been suggested in the last three decades, each one is confronting with limitations. CRISPR-Cas complex is a bacterial-derived system which made a breakthrough in the area of genome editing. This paper presents a brief history of CRISPR genome editing and discusses thoroughly how it works in bacteria and mammalians. At the end, some applications and challenges of this growing research area are also reviewed. In addition to moving the boundaries of genetics, CRISPR-Cas can also provide the ground for fundamental advances in other fields of biological sciences.
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http://dx.doi.org/10.4103/abr.abr_41_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712897PMC
August 2019
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