Publications by authors named "Massoud Houshmand"

142 Publications

Analysis of the HEXA, HEXB, ARSA, and SMPD1 Genes in 68 Iranian Patients.

J Mol Neurosci 2021 Sep 23. Epub 2021 Sep 23.

Department of Medical Genetics, National Institute for Genetic Engineering and Biotechnology (NIGEB), 14965/161, Tehran, Iran.

Lysosomal storage diseases (LSDs) are known as genetic disorders with an overall prevalence of 1 per 7700 live births. Sphingolipidosis, which is a subgroup of LSDs, is resulted from mutations in the coding genes of specific enzymes of sphingolipid hydrolases. The current study aimed to provide additional knowledge on the genotype of sphingolipidoses disease among Iranian patients affected by the disease. In this research, we studied 68 unrelated Iranian patients diagnosed with one kind of sphingolipidoses from 2014 to 2019. Thereafter, genomic DNA was isolated from their peripheral blood leukocytes samples in EDTA in terms of the manufacturer's protocol. All the coding exons and exon-intron boundaries of the related genes were sequenced and then analyzed using the NCBI database. Finally, they were reviewed using some databases such as the Human Gene Mutation Database (HGMD) and ClinVar ( https://www.ncbi.nlm.nih.gov/clinva ). By studying 22 MLD patients, 18 different variations of the ARSA gene were found, one of which was new including, named as c.472 T > G p. (Cys158Gly). Out of 15 Sandhoff disease (SD) patients, 11 different variations of the HEXB gene were found. Correspondingly, the c.1083-2delA was not reported earlier. By investigating 21 Iranian patients with Tay-Sachs disease (TSD), one new variant was found as c.622delG. The study of 10 Niemann-Pick disease A/B (NPDA/B (patients has led to the identification of 9 different SMPD1 gene variations, among which 3 variations were novel mutations. The results of the present study can be expanded to the genotypic spectrum of Iranian patients with MLD, SD, TSD, and NPD diseases and also used to innovate more effective methods for the detection of genetic carriers as well as diagnosing and counseling of Iranian patients affected with these disorders.
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http://dx.doi.org/10.1007/s12031-021-01907-6DOI Listing
September 2021

The effect of CHRNA3 rs1051730 C>T and ABCB1 rs3842 A>G polymorphisms on non-small cell lung cancer and nicotine dependence in Iranian population.

Heliyon 2021 Sep 24;7(9):e07867. Epub 2021 Aug 24.

Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran.

Aims: Lung cancer is still the leading cause of cancer mortality in all over the world. Nicotine and its derivatives are the most well-known carcinogens that participate in both etiology and progression of lung cancer. The objective of the current study was to investigate whether single nucleotide polymorphisms (SNPs) rs1051730C > T in CHRNA3 and rs3842A > G in ABCB1, two genes contributing in the mechanism of disposition and metabolism of nicotine and its derivatives, could modify the risk of developing lung cancer, as well as nicotine dependence in Iranian.

Main Methods: The genotyping analysis for these two SNPs was conducted in a case-control study of 108 lung cancer cases and 120 healthy controls using ARMS-PCR and Tetra-primer ARMS-PCR techniques. The correlation between studied SNPs and lung cancer was assessed by the regression analysis.

Key Findings: We observed a significant association between lung cancer and rs1051730C > T by using four genetic models: allele (OR:1.83; 95% CI:1.24-2.6; p = 0.002), dominant (OR: 2.19; 95% CI:1.27-3.78; p = 0.005), recessive (OR: 2.25; 95% CI: 1.02-4.95; p = 0.043) and additive (TT vs CC: OR:3.25; 95% CI:1.38-7.60; p = 0.007, CT vs CC: OR:1.96; 95% CI:1.10-3.48; p = 0.021). Furthermore, a significant association between this variant and nicotine dependence (OR: 2.27; 95% CI: 1.52-3.39; p = 0.00005) was reported. However, no association was found for rs3842A > G.

Significance: The results suggested that the CHRNA3 rs1051730C > T via a smoking-dependent manner could modify susceptibility to lung cancer among Iranian population.
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http://dx.doi.org/10.1016/j.heliyon.2021.e07867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426517PMC
September 2021

Investigating the Variation of TREC/KREC in Combined Immunodeficiencies.

Iran J Allergy Asthma Immunol 2021 Aug 7;20(4):402-412. Epub 2021 Aug 7.

Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

T-cell receptor excision circles (TREC)/Kappa-deleting recombination excision circles (KREC) assay has been recently recognized for detecting patients with primary (T- and/or B-cell) immunodeficiency (PID). We aimed to investigate the alterations of these biomarkers in some combined immunodeficiency patients compared to the healthy controls in different age groups. TREC and KREC were assessed in a total of 82 PID patients, most of them with exact genetic diagnosis (3 months to 42 years); using quantitative real-time-polymerase chain reaction (PCR). Patients had a final diagnosis of common variable immunodeficiency (n=23), ataxia-telangiectasia (AT) (n=17), hyper-IgE syndrome (HIES) (7 with DOCK8 deficiency, 4 with signal transducer and activator of transcription 3 (STAT3) deficiency, and 8 children with unknown genetic defects), Wiskott-Aldrich syndrome (WAS) (n=20), purine nucleoside phosphorylase (PNP)deficiency(n=1), dedicator of cytokinesis2 (DOCK2) deficiency (n=1), recombinase activating gene1 (RAG1) deficiency (n=1). Very low to zero amounts of TREC and/or KREC were detected in 14 out of 23 cases of common variable immunodeficiency (CVID), 14 out of 17 cases of AT, 8 out of 20 cases of WAS, 6 out of 7 cases of DOCK8-deficiency patients, 4 out of 8 cases of HIES with unknown genetic defects and all patients with defects in DOCK2, PNP, and RAG1. STAT3-deficient patients were normal for both biomarkers. All patients showed a significant difference in both markers compared to age-matched healthy controls. Our findings highlight that apart from severe types of T/B cell defects, this assay can also be used for early diagnosis the patients with late-onset of disease and even PIDs without a positive family history.
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August 2021

miR-324-3p and miR-508-5p expression levels could serve as potential diagnostic and multidrug-resistant biomarkers in childhood acute lymphoblastic leukemia.

Leuk Res 2021 Oct 12;109:106643. Epub 2021 Jun 12.

Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran. Electronic address:

Acute lymphoblastic leukemia (ALL) is one of the most frequent hematological malignancies in children, representing approximately 25 % of all pediatric cancers. Despite striking advances in ALL treatments, a small population of patients does not still respond to chemotherapy, raising the number of deaths in children. ABC transporters are one of the major causes of multidrug resistance (MDR) in cancers and overexpression of ABCA3 is directly associated with increased chemo-resistance in pediatric ALL. Here, we aimed to identify the microRNAs (miRNAs) which may regulate the expression of ABCA3 in childhood ALL. Bone marrow samples from a total of 50 ALLs and 59 controls were collected and after in silico and literature search, miR-324-3p and miR-508-5p were nominated from a list of putative miRNAs targeting ABCA3. Our qPCR analysis showed a low expression profile of selected miRNAs in pediatric ALL patients compared with non-cancer controls. Furthermore, we found that both miR-324-3p and miR-508-5p were significantly differentially expressed between patients with positive and negative minimal residual disease (MRD + vs MRD-) after one year of chemotherapy while only miR-508-5p was underexpressed in relapsed ALL patients. Additionally, a negative correlation was identified between the expression of these two miRNAs and ABCA3, supporting the regulatory effect of them on drug resistance through interacting with ABCA3. Overall, we suggested miR-324-3p and miR-508-5p as potential diagnostic and drug-resistant biomarkers in pediatric ALL. Moreover, our findings presented miR-508-5p to behave as a promising relapsed indicator in childhood ALL which can be applied in the development of novel therapeutic strategies.
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http://dx.doi.org/10.1016/j.leukres.2021.106643DOI Listing
October 2021

CAG repeats and one polymorphism in androgen receptor gene are associated with renal calcium stone disease.

Urologia 2021 May 19:3915603211017885. Epub 2021 May 19.

Urology and Nephrology Research Center (UNRC), Shahid Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran.

Purpose: Evidence suggests that androgens can be involved in the pathogenesis of renal stones. This study aimed at investigating coding region polymorphisms and CAG repeats in androgen receptor (AR) and their association with active renal calcium stone disease.

Materials And Methods: Male patients with calcium kidney stones ( = 106) with at least two episodes of stone recurrence or size increase during the past 5 years (ASF) were enrolled from December 2008 to April 2009. Control individuals were recruited after matching for age and gender from healthy individuals without current stone or history of stone disease. Genetic sequencing and single strand conformational polymorphism (SSCP) were used to determine AR polymorphisms in the patients and controls.

Results: Two polymorphisms were identified in the AR gene: Silent G to A polymorphism in the first exon of the AR gene and C to G polymorphism in intron 4. CAG repeats ranged from 12 to 37. The C/G polymorphism in intron 4 and CAG repeats were associated with the status of active renal calcium stone disease (all < 0.05). The CC variant of C/G polymorphism was not observed in patients with stone disease. CAG repeats less than 20 and more than 28 were mostly observed in ASF patients ( < 0.05).

Conclusions: CAG repeats and intron 4 C/G polymorphism in the AR gene have an association with renal calcium stone disease.
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http://dx.doi.org/10.1177/03915603211017885DOI Listing
May 2021

Correlation between and Polymorphisms and the Susceptibility to Breast Cancer.

Rep Biochem Mol Biol 2020 Oct;9(3):291-296

Department of Molecular Biology, Ahar Branch Islamic Azad University, Ahar, Iran.

Background: Breast cancer is classified as one of the common cancers among women worldwide. Within numerous genetic factors involved in the development of breast cancer, and genes are both located on breast cancer susceptibility locus. While the SNP in gene has a twilight association with breast cancer in different populations, polymorphisms have been reported to associate with breast tumor appearance in Asian, European, and African ancestry populations. The present report was designed a case-control group aimed at assessing the association of these two SNPs with breast cancer risk in the Iranian population.

Methods: In the case-control study of and polymorphisms in 100 women with breast cancer and 100 healthy women were examined by Tetra Arms PCR. Data collected using SPSS software and chi-square test and correlation coefficient were used for statistical analysis.

Results: The results of current study showed that the Chi-square of and polymorphism genotypes in breast cancer, were reported to be 51.613 and 47.920, respectively. Also there has been a significance level of both polymorphisms resulting in the frequency of genotypes in these two polymorphisms between case and control group.

Conclusion: Our finding thus suggested that in both polymorphisms, homozygote genotype showed strong correlation with cancer susceptibility. While, TT genotype in showed significant association with pathogenic properties, in the case of genotypes CC, and in second place, TT showed similar correlation.
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http://dx.doi.org/10.29252/rbmb.9.3.291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816788PMC
October 2020

Novel Homozygous Pathogenic Mutations of LAMA 2 Gene in Patients with Congen ital Muscular Dystrophy.

Iran J Child Neurol 2021 ;15(1):101-106

National Institute of Genetic Engineering and Biotechnology, Tehran, Iran.

The laminin α2 subunit is a protein encoded by the laminin α2 gene(LAMA2) which has the role of adhesion (attachment of cells to one another). Genetics consideration showed that mutation in LAMA2 caused a collection of muscle-wasting conditions called muscular dystrophy. This disorder causes disconnection of muscular cells and degeneration of the musculoskeletal system. In this study, we defined the molecular consideration of three patients with laminin α2 deficiency by clinical presentations of congenital muscular dystrophy. In this regard, 65 exons of the LAMA2 gene were amplified by polymerase chain reaction. Moreover, multiple ligation-dependent probe amplification and next generation sequencing (NGS) were carried out for all the patients. Because of NGS negativity, gene sequencing was performed. Results of searching for rearrangements of the LAMA2 gene enabled us to recognize homozygous pathogenic mutations c.2049_c.2050del, c.7156-2A>G, and c,1303C>T. These mutations produce an out-of-frame transcript that will be degraded by nonsense mediated decay. Therefore, we think these changes are pathogenic ones.
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http://dx.doi.org/10.22037/ijcn.v15i1.21649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856435PMC
January 2021

The Critical Role of Prenatal Genetic Study in Prevention of Primary Immunodeficiency in High-risk Families: The Largest Report of 107 Cases.

Iran J Allergy Asthma Immunol 2020 Oct 18;19(5):478-483. Epub 2020 Oct 18.

Immunology, Asthma and Allergy Research Institute, Children's Medical Center Hospital, Tehran University of Medical Sciences, Tehran, Iran AND Department of Immunology and Allergy, Children's Medical Center Hospital, Tehran University of Medical Sciences, Tehran, Iran.

This study aims to investigate the role of prenatal diagnosis (PND) in Iranian couples with a previous history of primary immunodeficiency disorders (PIDD) in their family. All referred couples with a family history of PIDD and a tendency for PND were included in this project. Based on gestational age, chorionic villus sampling (CVS) was performed to analyze the molecular defect of the fetus according to the previous gene defect of the affected case in the family. Postnatal confirmation was performed by immunological screening tests. In a total of 100 cases, CVS was not evaluated in 19 patients due to unwillingness (n=5), late prenatal referral (n=7), miscarriage before CVS (n=3), and female fetus with x-linked diseases in previous children (n=4). In the remaining 81 patients, heterozygous and homozygous mutations were found in 33 and 23 cases, respectively. The hemizygous mutation was obtained in 6 and no pathogenic mutations were found in 19 individuals. Postnatal evaluations revealed that a total of 65 babies were healthy, 32 fetuses were aborted (3 cases before CVS, 2 spontaneous abortions of a healthy and as affected fetus in the CVS subgroup, and 27 cases were aborted due to therapeutic causes). One fetus from the heterozygous subgroup was spontaneously aborted with severe combined immunodeficiency (SCID) and one fetus from the homozygous subgroup that was supposed to be healthy was affected by the autosomal dominant-chronic granulomatous disease (AR-CGD). The diagnostic error was 1.2%. PND is highly recommended in families with a history of PID in their previous child to prevent an affected baby being born and to reduce the government, family, and personal burden of these diseases.
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http://dx.doi.org/10.18502/ijaai.v19i5.4463DOI Listing
October 2020

A case report of congenital myasthenic syndrome caused by a mutation in theCHRNE genein the Iranian population.

Iran J Child Neurol 2020 ;14(4):87-94

National Institute of Genetic Engineering and Biotechnology, Tehran, Iran.

Congenital myasthenic syndrome (CMS) refers to a heterogeneous group of inherited disorders, characterized by defective transmissionat the neuromuscular junction (NMJ). Patients with CMS showed similar muscle weakness, while other clinical manifestations are mostly dependent on genetic factors. This disease,caused bydifferent DNA mutations, is genetically inherited. It is also associated with mutations of genes at NMJ, involving the acetylcholine receptor (AChR) subunits. Here, we present the case ofa five-year-old Iranian boywith CMS, undergoingtargeted sequencing of a panel of genes, associated with arthrogryposis and CMS. The patient had six affected relatives in his genetic pedigreechart. The investigations indicated a homozygous single base pair deletion at exon 12 of the gene (chr17:4802186delC).This region was conserved across mammalian evolution and was not submitted to the 1000 Genomes Project database.Overall, the variant may beclassified as a significant variant in the etiology of CMS.It can besuggested thatthe Iranian CMS population carry regional pathogenic mutations, which can be detected viatargeted and whole genome sequencing.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660024PMC
January 2020

Association of rs12487066, rs12044852, rs10735781, rs3135388, rs6897932, rs1321172, rs10492972, and rs9657904 Polymorphisms with Multiple Sclerosis in Iranian Population.

Oman Med J 2020 Jul 20;35(4):e150. Epub 2020 Jul 20.

Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran.

Objectives: Multiple sclerosis (MS) is a chronic disease of the central nervous system. The pathogenesis of MS is best described by a multifactorial model incorporating interactions between genetic and environmental factors with the role of genetic factors increasingly taken into account. The main goal of this study was to investigate the associations of rs12487066, rs12044852, rs10735781, rs3135388, rs6897932, rs1321172, rs10492972, and rs9657904 polymorphisms with MS in the Iranian population.

Methods: A total of 83 patients with MS (82.0% female and 18.0% male; mean age = 35.2±8.6 years) and 100 physically and mentally healthy subjects (81.0% female and 19.0% male; mean age = 40.4±6.4 years) were selected using convenient sampling. A 5 mL blood sample was taken from each case and control patient. We used the tetra-primer ARMS-PCR method to genotype the desired polymorphisms. The associations between polymorphisms and the disease were studied based on codominant, dominant, recessive, and overdominant models.

Results: The rs10735781 polymorphism was codominantly ( 0.029), overdominantly ( 0.008), and dominantly ( 0.009) associated with the disease. The rs6897932 was also found to be codominantly ( 0.012), dominantly ( 0.019), and recessively ( 0.011) associated with the disease.

Conclusions: We found an association between the rs10735781 and rs6897932 polymorphisms on the and genes, respectively, with increased MS in the Iranian population. Therefore, single nucleotide polymorphisms in the and genes can be considered a prognostic marker of MS.
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http://dx.doi.org/10.5001/omj.2020.69DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374718PMC
July 2020

Association of Obesity-Related Genetic Variants (FTO and MC4R) with Breast Cancer Risk: A Population-Based Case-Control Study in Iran.

Iran J Biotechnol 2019 Dec 1;17(4):e2460. Epub 2019 Dec 1.

Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran.

Background: Heterogeneous breast cancer is the most common cause of cancer-related mortality. Obesity defined by BMI is a known major risk factor for breast cancer.

Objectives: The purpose of this study was to explore the role of obesity related-polymorphisms rs9939609 Fat Mass and Obesity-associated (FTO) and rs17782313 in breast cancer development.

Materials And Methods: Matched peripheral blood serum was obtained from 64 breast cancer patients and 83 normal controls. Height and weight were measured to calculate BMI. All were genotyped for the SNPs rs9939609 and rs17782313 using a Tetra-primer ARMS-PCR method. For statistical analysis, the chi-square test and SPSS software were used.

Results: In subgroup analyses defined by BMI, rs9939609 genotypes (TT/AA/AT) were significantly associated with the risk of breast cancer only in non-obese subjects ( < 0.005). TT genotypes of rs17782313 in non-obese and genotypes TT/CC in the overweight group were also statistically associated with breast cancer ( < 0.005). No significant associations between any variants and breast cancer risk were seen in obese subjects.

Conclusion: Based on the absence of an association between obesity-related SNPs and breast cancer in obese subjects, it is proposed that weight gain in Iranian women will help prevent breast cancer risk. The result help for preparing and designing a safe and versatile recombinant drug in future.
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http://dx.doi.org/10.30498/IJB.2019.99594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357694PMC
December 2019

Boiss. Essential Oil Induce Apoptosis in Two Human Colon Cancer Cell Lines (HCT116 & SW48).

Iran J Public Health 2020 Apr;49(4):753-762

Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran.

Background: Boiss. is known by the common Persian name "", is one of the best-known medicinal herbs belonging to the Labiatae (Lamiaceae) family. The aim of this study was to evaluate the anticancer effects and the underlying mechanisms of how Boiss., essential oil induced apoptosis in the human colorectal tumor cell lines (HCT116 & SW48).

Methods: This study was conducted in National Institute of Genetic Engineering and Biotechnology (NIGEB) (Tehran, Iran) from 2017 to 2019. The cytotoxicity of this essential oil was assessed by 3- (4,5-di-methylthiazol-2-yl)- 2,5-diphenyltetra-zolium bromide MTT) assay, trypan blue exclusion, and colony formation assays. We assessed apoptosis and measure intracellular reactive oxygen species (ROS) by flow cytometry. Then gene expression was analyzed by Quantitative Real-Time RT-PCR.

Results: Boiss., essential oil time- and dose-dependently inhibits cell proliferation and also induced apoptosis in both cell lines via UCP-related mitochondrial pathway by the induction of intracellular ROS.

Conclusion: Boiss., essential oil could be a good candidate for use as an inhibitor of the growth of colorectal tumor cells.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283189PMC
April 2020

and are Associated with Type 2 Diabetes Mellitus in Iranian Patients.

Diabetes Metab Syndr Obes 2020 24;13:897-906. Epub 2020 Mar 24.

Department of Epidemiology, School of Health, Arak University of Medical Sciences, Arak, Iran.

Background: Type 2 diabetes mellitus (T2DM) is a serious public health issue with significantly increasing rates across the world. The genome-wide association studies (GWAS) have previously manifested involved genes that remarkably enhance the risk of T2DM. In this study, the association of common variants with T2DM risk has been identified among Iranian population from Tehran province of Iran.

Methods: Here, the association of refSNPs with T2DM risk was examined on peripheral blood samples of 268 individuals including control group and patients with T2DM using the tetra amplification refractory mutation system (ARMS) methods and direct genomic DNA sequencing.

Results: Our study demonstrated that rs13266634 (T/C), rs10946398 (A/C), rs7903146 (C/T), rs2237892 (T/C), and rs1470579 (A/C) polymorphisms are significantly associated with type 2 diabetes, but no significant association was identified for FTO rs8050136 and MTNR1B rs10830963 polymorphisms.

Conclusion: The prediction of refSNPs is remarkably needed for pharmacogenetics and pharmacogenomic approaches, in which the information would be useful for clinicians to optimize therapeutic strategies and adverse drug reactions in patients with T2DM.
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http://dx.doi.org/10.2147/DMSO.S225968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102914PMC
March 2020

Investigation of Mutations in Exon 14 of Gene and Exon 7 of Gene in Iranian Charcot-Marie-Tooth Disease Type 4 (CMT4D) Patients.

Iran J Child Neurol 2020 ;14(2):93-100

Department of National Institute of Genetic Engineering and Biotechnology, Tehran, Iran.

Objectives: Charcot-Marie-tooth disease type 4 (CMT4D) is an autosomal recessive form of Charcot-Marie-tooth disease with an earlier age of onset and greater severity, compared to other types of this disease. CMT4C and CMT4D are the most prevalent subtypes in Mediterranean countries due to the higher rate of consanguineous marriage. In this study, we aimed to identify p.R148X mutation in gene and p.R1109X mutation in gene (responsible for CMT4D and CMT4C, respectively) and to investigate other possible nucleotide changes in exon 14 of gene and exon 7 of gene in an Iranian population.

Materials & Methods: A total of 24 CMT4D patients, who were referred to Iran Special Medical Center, were clinically and electrophysiologically evaluated in this study. DNA was extracted from the patients' blood samples. Next, polymerase chain reaction (PCR) assay was carried out, and the products were sequenced and analyzed in FinchTV software.

Results: None of the target mutations were found in this study. Sequencing of gene showed SNP rs1025476 (g.57975C>T) in 21 (87.5%) patients, including 7 homozygous and 14 heterozygous individuals.

Conclusion: Despite the high rate of mutations in some populations, it seems that they are very rare in Iranian CMT4D patients. Regarding the association of SNP rs1025476 with CMT4D, further assessments are needed to reach a better understanding of genetic markers and their genetic features and to propose better diagnostic and treatment plans for the Iranian population.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085125PMC
January 2020

Clinical and Genetic Analysis of Nine Suspected Familial Haemophagocytic Lymphohistiocytosis Patients for MUNC13-4 Deficiency and Introducing Four Novel Mutations in UNC13D.

Iran J Allergy Asthma Immunol 2019 Oct 23;18(5):487-492. Epub 2019 Oct 23.

Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

Familial haemophagocytic lymphohistiocytosis (FHL) is a rare disorder of immune dysregulation. FHL inherited in an autosomal recessive pattern is classified into five subtypes based on underlying genetic defects. Mutations in four genes including PRF1, UNC13D, STX11 and STXBP2 are responsible for FHL2 to FHL5 respectively. The cause of FHL1 is associated with mutations in an unknown gene located at 9q21.3-22. This study aims to report the clinical features and genetic results of nine Iranian patients suffering from -haemophagocytic lymphohistiocytosis. Nine patients (five males and four females) suspected to FHL whose genetic evaluation of PRF1 and STX11 revealed no mutations, were entered the study to investigate UNC13D mutations. Primers were designed to amplify all coding regions and exon-intron boundaries of the gene. PCR products were then sequenced and analyzed by sequence analysis tools including BLAST. The most frequent clinical manifestations observed in the patients were fever and hepatosplenomegaly. In this study, five mutations were detected in UNC13D including four novel mutations (c.1434_1446delACCCATGGTGCAGinsTGGTGCT, c.1933C>T, c.1389+1G>C and c.2091+1G>A) besides to a previously reported deletion (c.627delT). The pathogenicity of the missense mutation was assessed using online prediction tools including SIFT and PolyPhen2. The study results may provide valuable information for genetic counseling especially for those who have a history of immunodeficiency diseases in their family and can be used for prenatal diagnosis.
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http://dx.doi.org/10.18502/ijaai.v18i5.1911DOI Listing
October 2019

An A10398G mitochondrial DNA alteration is related to increased risk of breast cancer, and associates with Her2 positive receptor.

Mitochondrial DNA A DNA Mapp Seq Anal 2020 01 4;31(1):11-16. Epub 2019 Dec 4.

Department of Medical Genetic, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran.

Breast cancer is the most common malignancy and the second leading cause of cancer deaths among women worldwide after lung cancer. Mitochondria play a central role in the regulation of cellular function, metabolism, and cell death in cancer cells. We aim to examine the mitochondrial polymorphisms of complex I in association with breast cancer in an Iranian cohort.This experimental study includes 53 patients with breast cancer and 35 healthy control patients. In addition, tumor-adjacent normal breast tissue was obtained from each patient. The DNA of the tissue cells was extracted and analyzed for complex I mutations using a PCR sequencing method. Our results show 94 mtDNA complex I variants in tumor tissues. A10398G was the most prevalent polymorphism and strongly correlated with Her2 receptor in tumor tissue samples. Mitochondrial DNA (mtDNA) mutations have been widely linked to the etiology of numerous disorders. The mtDNA mutations screening on A10398G along with other mutations might provide insight on the role of mitochondrial mutations in breast cancer.
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http://dx.doi.org/10.1080/24701394.2019.1695788DOI Listing
January 2020

Role of and in Iranian Nonsyndromic Hearing Impairment: From Molecular Analysis to Literature Reviews.

Fetal Pediatr Pathol 2020 Feb 19;39(1):1-12. Epub 2019 Jun 19.

ENT and Head & Neck Research Center and Department, The Five Senses Institute, Hazrat Rasool Akram Hospital, Iran University of Medical Sciences, Tehran, Islamic Republic of Iran.

Hearing impairment (HI) is a heterogeneous disorder. and genes are typically the first line of genetic screening before proceeding to any massive parallel sequencing. We evaluated the clinical utility of and testing in the Iranian population. and were sequenced. PubMed and Google Scholar were searched for Iranian publications on deletions in the DFNB1 locus. We detected mutations of in 16.5%, and no mutations of Literature review revealed no reports of mutations of in the Iranian population. This data and literature reviews indicate that is not commonly responsible for Iranian nonsyndromic HI. Hence, the clinical utility of genetic analysis as a first line for HI evaluation does not have the same utility as . The study is consistent with recent studies emphasizing the role of ethnicity in the selection of HI genetic testing strategy.
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http://dx.doi.org/10.1080/15513815.2019.1627625DOI Listing
February 2020

Mitochondrial Polymorphisms, in The D-Loop Area, Are Associated with Brain Tumors.

Cell J 2019 Oct 15;21(3):350-356. Epub 2019 Jun 15.

Department of Medical Genetics, National Institutes for Genetic Engineering and Biotechnology, Tehran, Iran.

Objective: This study was carried out to evaluate the relationship between mtDNA D-loop variations and the pathogenesis of a brain tumor.

Materials And Methods: In this experimental study, 25 specimens of brain tumor tissue with their adjacent tissues from patients and 454 blood samples from different ethnic groups of the Iranian population, as the control group, were analysed by the polymerase chain reaction (PCR)-sequencing method.

Results: Thirty-six variations of the D-loop area were observed in brain tumor tissues as well as the adjacent normal tissues. A significant difference of A750G (P=0.046), T15936C (P=0.013), C15884G (P=0.013), C16069T (P=0.049), T16126C (P=0.006), C16186T (P=0.022), T16189C (P=0.041), C16193T (P=0.045), C16223T (P=0.001), T16224C (P=0.013), C16234T (P=0.013), G16274A (P=0.009), T16311C (P=0.038), C16327T (P=0.045), C16355T (P=0.003), T16362C (P=0.006), G16384A (P=0.042), G16392A (P=0.013), G16394A (P=0.013), and G16477A (P=0.013) variants was found between the patients and the controls.

Conclusion: The results indicated individuals with C16069T [odds ratio (OR): 2.048], T16126C (OR: 2.226), C16186T (OR: 3.586), G16274A (OR: 4.831), C16355T (OR: 7.322), and T16362C (OR: 6.682) variants with an OR more than one are probably associated with a brain tumor. However, given the multifactorial nature of cancer, more investigation needs to be done to confirm this association.
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http://dx.doi.org/10.22074/cellj.2019.5947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582428PMC
October 2019

Genetic and molecular findings of 38 Iranian patients with chronic granulomatous disease caused by p47-phox defect.

Scand J Immunol 2019 Jul 25;90(1):e12767. Epub 2019 Apr 25.

Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

One of the components of NADPH oxidase is p47-phox, encoded by NCF1 gene. This study aims to find new genetic changes and clinical features in 38 Iranian patients with autosomal recessive chronic granulomatous disease (AR-CGD) caused by NCF1 gene defect. Patients who had abnormal NBT and DHR-1,2,3 assay with loss of p47-phox in Western blotting were included in this study. After recording demographic and clinical data, PCR amplification was performed followed by direct sequencing for all exons and exon-intron boundaries. The most common form of CGD in Iran was AR-CGD due to consanguinity marriages. Among patients with AR-CGD, NCF1 deficiency was found to be more common than other forms. Cutaneous involvements (53%), pulmonary infections (50%) and lymphadenopathy (29%) were more prevalent than other clinical manifestations of CGD. Mutation analysis of NCF1 gene identified five different mutations. Homozygous delta GT deletion (c.75_76delGT) was the most frequent mutation and was detected in more than 63% of families. Six families had a nonsense mutation in exon 7 (c.579G > A). Two novel mutations were found in exon 4 in two families, including a missense mutation (c.328C > T) and a nine-nucleotide deletion (c.331_339delTGTCCCCAC). Genetic detection of these mutations may result in early diagnosis and prevention of possible complications of the disease. This could be useful for timely decision-making for haematopoietic stem cell transplantation and for carrier detection as well as prenatal diagnosis of next children in the affected families. Our findings might help to predict outcomes, raise awareness and help effective treatment in these patients.
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http://dx.doi.org/10.1111/sji.12767DOI Listing
July 2019

Diagnostic Value of Non-Invasive Prenatal Screening of β-thalassemia by Cell Free Fetal DNA and Fetal NRBC.

Curr Mol Med 2019 ;19(2):105-111

PhD student, Department of Clinical Biochemistry, School of Medicine, Tarbiat Modares University, Tehran, Iran.

Background: Beta thalassemia is a common disorder with autosomal recessive inheritance. The most prenatal diagnostic methods are the invasive techniques that have the risk of miscarriage. Now the non-invasive methods will be gradually alternative for these invasive techniques.

Objective: The aim of this study is to evaluate and compare the diagnostic value of two non-invasive diagnostic methods for fetal thalassemia using cell free fetal DNA (cff-DNA) and nucleated RBC (NRBC) in one sampling community.

Methods: 10 ml of blood was taken in two k3EDTA tube from 32 pregnant women (mean of gestational age = 11 weeks), who themselves and their husbands had minor thalassemia. One tube was used to enrich NRBC and other was used for cff-DNA extraction. NRBCs were isolated by MACS method and immunohistochemistry; the genome of stained cells was amplified by multiple displacement amplification (MDA) procedure. These products were used as template in b-globin segments PCR. cff-DNA was extracted by THP method and 300 bp areas were recovered from the agarose gel as fetus DNA. These DNA were used as template in touch down PCR to amplify b-globin gen. The amplified b-globin segments were sequenced and the results compared with CVS resul.

Results: The data showed that sensitivity and specificity of thalassemia diagnosis by NRBC were 100% and 92% respectively and sensitivity and specificity of thalassemia diagnosis by cff-DNA were 100% and 84% respectively.

Conclusion: These methods with high sensitivity can be used as screening test but due to their lower specificity than CVS, they cannot be used as diagnostic test.
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http://dx.doi.org/10.2174/1566524019666190226124135DOI Listing
June 2020

Evaluation of rs9939609 and rs17782313 Polymorphisms as Prognostic Biomarkers of Obesity: A Population-based Cross-sectional Study.

Oman Med J 2019 Jan;34(1):56-62

Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran.

Objectives: Obesity is a significant risk factor for a number of chronic diseases, including diabetes, cardiovascular diseases, and cancer. Obesity usually results from a combination of causes and contributing factors, including genetics and lifestyle choices. Many studies have shown an association of single nucleotide polymorphisms (SNPs) in the fat mass and obesity-associated () and the melanocortin-4 receptor () genes with body mass index (BMI). Therefore, recognizing the main genes and their relevant genetic variants will aid prediction of obesity risk. The aim of our study was to investigate the frequency of rs9939609 and rs17782313 polymorphisms in and genes in an Iranian population.

Methods: We enrolled 130 obese patients and 83 healthy weight controls and calculated their BMI. Genomic DNA was extracted from peripheral blood and the frequency of rs9939609 and rs17782313 polymorphisms in and genes was determined using the tetra-primer amplification refractory mutation system-polymerase chain reaction (ARMS-PCR).

Results: Significant associations were found between rs9939609 and BMI. Where homozygous risk allele carriers (A-A) have significant higher odds ratio (OR) of being obese than individuals with normal BMI (OR = 6.927, < 0.005, 95% confidence interval (CI): 3.48-13.78). No significant correlation between rs17782313 and obesity were observed when compared to healthy weight individuals. Although subjects with C-C genotype had higher odds of obesity (OR = 1.889, 0.077, 95%CI: 0.92-3.84).

Conclusions: This study shows a relationship between polymorphism and increased BMI, therefore, SNP in the gene influence changes in BMI and can be considered a prognostic marker of obesity risk.
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http://dx.doi.org/10.5001/omj.2019.09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330185PMC
January 2019

Genipin induces cell death via intrinsic apoptosis pathways in human glioblastoma cells.

J Cell Biochem 2018 Aug 30. Epub 2018 Aug 30.

Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Zabol, Zabol, Iran.

Genipin, a compound derived from Gardenis jasminoides Ellis fruits, was demonstrated to be the specific uncoupling protein 2 (UCP2) inhibitor. UCP2 is a mitochondrial carrier protein that creates proton leaks across the inner mitochondrial membrane, thus uncoupling oxidative phosphorylation from adenosine triphosphate (ATP) synthesis. Several studies revealed that UCP2 is broadly over-expressed in leukemia, colorectal, lung, ovarian, prostate, testicular, and bladder cancers. However, the effect of genipin still needs to be elucidated in neurological malignancies. In this study, we investigated the anticancer effect of genipin in U87MG and A172 cell lines. The anticancer effect of genipin on these cell lines was measured by microculture tetrazoliumtest (MTT), Trypan blue exclusion, and colony formation assays, in the presence of various concentrations of genipin at different time intervals. We assessed apoptosis and measure intracellular reactive oxygen species (ROS) by flow cytometry. Expression of UCP2 and some of the genes involved in apoptosis was analyzed by real-time quantitative polymerase chain reaction (PCR). Results of the MTT assay showed that genipin moderately reduced metabolic activity of both cell lines in dose- and time-dependent manner. Result of Trypan blue exclusion test indicated that the viable cell count decreased in the treated group in a concentration-dependent manner. Genipin also significantly decreased colony formation ability of these cells in a concentration-dependent manner. Result of morphological changes showed that there were significant differences in cell number and morphology in treated groups as compared with the untreated groups. Flow cytometric analysis of U87MG and A172 cells with annexin V/propidium iodide staining, 48 hours after treatment with genipin, displays 22.4% and 26.1% apoptotic population, respectively, in treated cells, in comparison to 7.42% and 9.31% apoptotic cells of untreated cells. After treatment, UCP2 and B-cell lymphoma 2 (BCL ) genes are downregulated, and BCL associated X protein, BCL antagonist/killer, BCL interacting killer, and Cytochrome c genes are upregulated. Genipin treatment increased mitochondrial ROS levels and also induced apoptosis through caspase-3 upregulation. In conclusion, the antiproliferative effects of genipin on the growth of both glioblastoma cell lines have been shown in all of these assays, and genipin profoundly induced apoptosis in both cell lines via the UCP2-related mitochondrial pathway through the induction of intracellular ROS.
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http://dx.doi.org/10.1002/jcb.27512DOI Listing
August 2018

Newborn screening using TREC/KREC assay for severe T and B cell lymphopenia in Iran.

Scand J Immunol 2018 Jun 26:e12699. Epub 2018 Jun 26.

Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

T-cell receptor excision circles (TRECs) and κ-deleting recombination excision circles (KRECs) are recently used for detection of T or B cell lymphopenia in neonates based on region-specific cutoff levels. Here, we report cutoffs for TREC and KREC copies useful for newborn screening and/or diagnosis of primary immunodeficiency diseases (PID) in Iran. DNA was extracted from a single 3.2 mm punch of dried blood spots collected from 2160 anonymized newborns referred to two major referral health centers between 2014 and 2016. For refinement of the cutoffs, 51 patients with a definite diagnosis of severe combined immunodeficiency, X-linked agammaglobulinaemia and combined immunodeficiency, including ataxia telangiectasia, human phosphoglucomutase 3 and Janus kinase-3 deficiency, as well as 47 healthy controls were included. Samples from patients with an X-linked hyper-IgM-syndrome, Wiskott-Aldrich syndrome and DNA ligase 4 deficiency were considered as disease controls. Triplex-quantitative real-time PCR was used. Cutoffs were calculated as TRECs < 11 and KRECs < 6 copies with an ACTB > 700 copies with sensitivity of 100% for TREC and 97% for KREC. Among thirty anonymized newborn samples (1.5%) with abnormal results for TREC and/or KREC, only twenty one available cases were retested and shown to be in the normal range except for three samples (0.15%). All of the patients with a definitive diagnosis were correctly identified based on our established TREC/KREC copy numbers. Determining cutoffs for TREC/KREC is essential for correctly identifying children with PID in newborn screening. Early diagnosis of PID patients enables appropriate measures and therapies like stem cell transplantation. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/sji.12699DOI Listing
June 2018

Mitochondrial G8292A and C8794T mutations in patients with Niemann-Pick disease type C.

Biomed Rep 2018 Jul 14;9(1):65-73. Epub 2018 May 14.

Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran 14965/161, Iran.

Niemann-Pick disease type C (NP-C) is a neurovisceral lipid storage disorder. At the cellular level, the disorder is characterized by accumulation of unesterified cholesterol and glycolipids in the lysosomal/late endosomal system. NP-C is transmitted in an autosomal recessive manner and is caused by mutations in either the (95% of families) or gene. The estimated disease incidence is 1 in 120,000 live births, but this likely represents an underestimate, as the disease may be under-diagnosed due to its highly heterogeneous presentation. Variants of adenosine triphosphatase (ATPase) subunit 6 and ATPase subunit 8 () in mitochondrial DNA (mtDNA) have been reported in different types of genetic diseases including NP-C. In the present study, the blood samples of 22 Iranian patients with NP-C and 150 healthy subjects as a control group were analyzed. The DNA of the blood samples was extracted by the salting out method and analyzed for mutations using polymerase chain reaction sequencing. Sequence variations in mitochondrial genome samples were determined via the Mitomap database. Analysis of sequencing data confirmed the existence of 11 different single nucleotide polymorphisms (SNPs) in patients with NP-C1. One of the most prevalent polymorphisms was the A8860G variant, which was observed in both affected and non-affected groups and determined to have no significant association with NP-C incidence. Amongst the 11 polymorphisms, only one was identified in the gene, while 9 including A8860G were observed in the gene. Furthermore, two SNPs, G8292A and C8792A, located in the non-coding region of mtDNA and the gene, respectively, exhibited significantly higher prevalence rates in NP-C1 patients compared with the control group (P<0.01). The present study suggests that there may be an association between mitochondrial mutations and the incidence of NP-C disease. In addition, the mitochondrial SNPs identified maybe pathogenic mutations involved in the development and prevalence of NP-C. Furthermore, these results suggest a higher occurrence of mutations in than in in NP-C patients.
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http://dx.doi.org/10.3892/br.2018.1095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007046PMC
July 2018

Mitochondrial Variants in Pompe Disease: A Comparison between Classic and Non-Classic Forms.

Cell J 2018 Oct 15;20(3):333-339. Epub 2018 May 15.

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

Objective: Pompe disease (PD) is a progressive neuromuscular disorder that is caused by glucosidase acid alpha (GAA) deleterious mutations. Mitochondrial involvement is an important contributor to neuromuscular diseases. In this study the sequence of MT-ATP 6/8 and Cytochrome C oxidase I/II genes along with the expression levels of the former genes were compared in classic and non-classic patients.

Materials And Methods: In this case-control study, the sequence of MT-ATP 6/8 and Cytochrome C oxidase was analyzed by polymerase chain reaction (PCR)-Sanger sequencing and expression of MT-ATP genes were quantified by real time-PCR (RT-PCR) in 28 Pompe patients. The results were then compared with 100 controls. All sequences were compared with the revised Cambridge reference sequence as reference.

Results: Screening of MT-ATP6/8 resulted in the identification of three novel variants, namely T9117A, A8456C and A8524C. There was a significant decrease in MT-ATP6 expression between classic (i.e. adult) and control groups (P=0.030). Additionally, the MT-ATP8 expression was significantly decreased in classic (P=0.004) and non-classic (i.e. infant) patients (P=0.013). In total, 22 variants were observed in Cytochrome C oxidase, five of which were nonsynonymous, one leading to a stop codon and another (C9227G) being a novel heteroplasmic variant. The A8302G in the lysine tRNA gene was found in two brothers in a pedigree, while a T7572C variant in the aspartate tRNA gene was observed in two brothers in another pedigree.

Conclusion: The extent of mitochondrial involvement in the classic group was more significant than in the non-classic form. Beside GAA deleterious mutations, it seems that mtDNA variants have a secondary effect on PD. Understanding, the role of mitochondria in the pathogenesis of Pompe may potentially be helpful in developing new therapeutic strategies.
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http://dx.doi.org/10.22074/cellj.2018.5238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004991PMC
October 2018

Analysis of partial AZFc (gr/gr, b1/b3, and b2/b3) deletions in Iranian oligozoospermia candidates for intracytoplasmic sperm injection (ICSI)

Turk J Med Sci 2018 Apr 30;48(2):251-256. Epub 2018 Apr 30.

Background/aim: Infertility is a main health issue. The human Y chromosome contains essential genes for spermatogenesis, especially those located on four major intervals defined as AZFa, AZFb, AZFc, and AZFd. A partial deletion of the AZFc region is reported as a significant risk factor for oligo-/azoospermia. The main purpose of this study was to investigate the prevalence of partial deletions in the AZFc region (gr/gr, b1/b3, and b2/b3) in Iranian oligozoospermic candidates for intracytoplasmic sperm injection. Materials and methods: Multiplex PCR was used to assess the micro and partial deletions in 60 oligozoospermia infertile and 80 fertile men. Results: Two cases (3.33%) showed AZFb deletion but no microdeletion was detected in the control samples. In the AZFc region, 20% of the patients showed deletions, in which 15% and 5% showed gr/gr and b2/b3 deletions, respectively. However, 10% of the healthy individuals also showed partial deletions, including gr/gr (7.5%) and b2/b3 (2.5%). No significant correlation was detected between the presence of gr/gr microdeletion in patients and controls (P > 0.05). Conclusion: Our study showed that the partial AZFc deletions are not associated with male infertility in Iranian subjects.
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http://dx.doi.org/10.3906/sag-1710-71DOI Listing
April 2018

Prevalence of the CYP2C19*2 (681 G>A), *3 (636 G>A) and *17 (‑806 C>T) alleles among an Iranian population of different ethnicities.

Mol Med Rep 2018 Mar 5;17(3):4195-4202. Epub 2018 Jan 5.

Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran 14965/161, Iran.

Polymorphisms in the cytochrome P (CYP) 450 family may cause adverse drug responses in individuals. Cytochrome P450 2C19 (CYP2C19) is a member of the CYP family, where the presence of the 681 G>A, 636 G>A and 806 C>T polymorphisms result in the CYP2C19*2, CYP2C19*3 and CYP2C19*17 alleles, respectively. In the current study, the frequency of the CYP2C19*2, CYP2C19*3 and CYP2C19*17 alleles in an Iranian population cohort of different ethnicities were examined and then compared with previously published frequencies within other populations. Allelic and genotypic frequencies of the CYP2C19 alleles (*2, *3 and *17) were detected using polymerase chain reaction (PCR)‑restriction fragment length polymorphism analysis, PCR‑single‑strand conformation polymorphism analysis and DNA sequencing from blood samples of 1,229 unrelated healthy individuals from different ethnicities within the Iranian population. The CYP2C19 allele frequencies among the Iranian population were 21.4, 1.7, and 27.1% for the CYP2C19*2, CYP2C19*3 and CYP2C19*17 alleles, respectively. The frequency of the homozygous A/A variant of the CYP2C19*2 allele was significantly high and low in the Lur (P<0.001) and Caspian (P<0.001) ethnicities, respectively. However, the frequency of the homozygous A/A variant of the CYP2C19*3 allele was not detected in the Iranian cohort in the current study. The frequency of the heterozygous G/A variant of the CYP2C19*3 allele had the significantly highest and lowest frequency in the Fars (P<0.001) and Lur (P<0.001) groups, respectively. The allele frequency of the homozygous T/T variant of the CYP2C19*17 allele was significantly high in the Caspian (P<0.001) and low in the Kurd (P<0.05) groups. The frequency of the CYP2C19 alleles involved in drug metabolism, may improve the clinical understanding of the ethnic differences in drug responses, resulting in the advancement of the personalized medicine among the different ethnicities within the Iranian population.
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http://dx.doi.org/10.3892/mmr.2018.8377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802190PMC
March 2018

Four novel mutations of the BCKDHA, BCKDHB and DBT genes in Iranian patients with maple syrup urine disease.

J Pediatr Endocrinol Metab 2018 Jan;31(2):205-212

Medical Genetics Research Center and Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad 9196773117, Iran.

Background: Maple syrup urine disease (MSUD) is a rare metabolic autosomal recessive disorder caused by dysfunction of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex. Mutations in the BCKDHA, BCKDHB and DBT genes are responsible for MSUD. The current study analyzed seven Iranian MSUD patients genetically and explored probable correlations between their genotype and phenotype.

Methods: The panel of genes, including BCKDHA, BCKDHB and DBT, was evaluated, using routine the polymerase chain reaction (PCR)-sequencing method. In addition, protein modeling (homology and threading modeling) of the deduced novel mutations was performed. The resulting structures were then analyzed, using state-of-the-art bioinformatics tools to better understand the structural and functional effects caused by mutations.

Results: Seven mutations were detected in seven patients, including four novel pathogenic mutations in BCKDHA (c.1198delA, c.629C>T), BCKDHB (c.652C>T) and DBT (c.1150A>G) genes. Molecular modeling of the novel mutations revealed clear changes in the molecular energy levels and stereochemical traits of the modeled proteins, which may be indicative of strong correlations with the functional modifications of the genes. Structural deficiencies were compatible with the observed phenotypes.

Conclusions: Any type of MSUD can show heterogeneous clinical manifestations in different ethnic groups. Comprehensive molecular investigations would be necessary for differential diagnosis.
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http://dx.doi.org/10.1515/jpem-2017-0305DOI Listing
January 2018

Glutaric AciduriaType 1: Clinical and Molecular Study in Iranian Patients, 3 Novel Mutations.

Iran J Child Neurol 2017 ;11(4):58-65

Pediatric Neurology Research Center, Research Institute for Children Health, ShahidBeheshti University of Medical Science, Tehran, Iran; School of Medicine, ShahidBeheshti University of Medical Science, Tehran, Iran.

Objective: Glutaricaciduria type 1 (GA1), is a rare, treatable neuro metabolic disease, due to gene mutation.In regions without neonatal blood screening (NBS), patients are diagnosed in symptomatic period. This study was carried out to assess patients with GA1 for clinical, biochemical, neuroimaging findings and GCDH gene mutations analysis.

Materials & Methods: In this cross-sectional study, clinical manifestation, neuroimaging and metabolic findings of eleven Iranian GA1 patients of MofidChildren's Hospital, Tehran, Iranbetween 2001 and 2011,were evaluated.Mutational analysis of the GCDH gene was performed on genomic DNA. Genomic DNA was extracted from peripheral lymphocytes using QIAamp DNA Micro Kit (Qiagen). All 11 exons and flanking intronic regions of the GCDH gene were amplified by polymerase chain reaction (PCR).

Results: All patients were diagnosed before 32 months old. Clinical presentations of GA1 include acute encephalopathic crisis and/or developmental delay and macrocephaly. Seven GCDH gene mutations were detected in our patients. The most frequent GCDH mutations occurred in exon7 then exon8, 10 and11. G244 C in exon7, R294 Q in exon8 and N373 S in exon 10 were three novel mutations. There was no correlation between of genotype and phenotype in our patients.

Conclusion: Physician must remember GA1 in differential diagnosis of acute encephalopathic crisis, macrocephaly, developmental delay, movement disorders such as dystonia and dyskinesia. Early detection, proper treatment and selective screening of patients' siblings can prevent neurologic disabilities.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703630PMC
January 2017
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