PubMed | Shahid Beheshti University of Medical Sciences, Tehran University of Medical Sciences, Pasteur Institute of Iran, Royan Institute for Stem Cell Biology and Technology and Kawsar Human Genetics Research Center
Type: | Journal: Mutation research | Year: 2016
Maple syrup urine disease (MSUD) is a rare inborn error of branched-chain amino acid metabolism. The disease prevalence is higher in populations with elevated rate of consanguineous marriages such as Iran. Different types of disease causing mutations have been previously reported in BCKDHA, BCKDHB, DBT and DLD genes known to be responsible for MSUD phenotype. In this study, two sets of multiplex polymorphic STR (Short Tandem Repeat) markers linked to the above genes were used to aid in homozygosity mapping in order to find probable pathogenic change(s) in the studied families. The families who showed homozygote haplotype for the BCKDHA gene were subsequently sequenced. Our findings showed that exons 2, 4 and 6 contain most of the mutations which are novel. The changes include two single nucleotide deletion (i.e. c. 143delT and c.702delT), one gross deletion covering the whole exon four c.(375+1_376-1)_(8849+1_885-1), two splice site changes (c.1167+1G>T, c. 288+1G>A), and one point mutation (c.731G>A). Computational approaches were used to analyze these two novel mutations in terms of their impact on protein structure. Computational structural modeling indicated that these mutations might affect structural stability and multimeric assembly of branched-chain -keto acid dehydrogenase complex (BCKDC).
Keshavarzi F.,Islamic Azad University at Sanandaj Branch |
Javadi G.R.,Islamic Azad University at Tehran |
Zeinali S.,Kawsar Human Genetics Research Center |
Zeinali S.,Pasteur Institute of Iran
Familial Cancer | Year: 2012
Breast cancer is the most common cancer in Iranian women (Mousavi et al in Asian Pac J Cancer Prev 9(2):275-278, 2008). Genetic predisposition accounts for 15% of all breast cancers and germline mutations in breast cancer susceptibility genes, BRCA1 and BRCA2 are responsible for a substantial proportion of high-risk breast and breast/ovarian cancer families (Collaborative Group on Hormonal Factors in Breast Cancer in Lancet 350:1047-1059, 1997; Lee et al in Int Nurs Rev 55:355-359, 2008; Hulka and Stark in Lancet 346:883-887, 1995; Kelsey in Epidemiol Rev 15:256-263, 1993; Tischer et al in J Biol Chem 266:11947-11954, 1991; Newman et al in: Proc Natl Acad Sci USA 85:3044-3048, 1988). Therefore, the aim of this study was to investigate mutations of BRCA1/2 in high risk Iranian families. We screened 85 patients who met our minimal criteria. The entire coding sequences and each intron/exon boundaries of BRCA1/2 genes were screened by direct sequencing. In the present study, we could detect the novel following mutations: p.Glu1735 p.Gly1140Ser, p.Ile26Val, p.Leu1418X, p.Glu23Gln, p.Leu3X, p.Asn1403His, p.Lys581X, p.Pro938Arg, p.Thr77Arg, p.Arg7Cys, p.Ser177Thr, IVS7+83(TT), IVS8-70(-CATT), IVS2+9(-GC), IVS1-20(-GA), IVS1-8(-AG), IVS2+24(AG), IVS5-8 (A-G), IVS2(35-39)TTcctatGAT in BRCA1 and p.Glu1391Gly, 1994-1995 (Ins A), IVS6-70-T>G in BRCA2. In agreement with findings in other populations, we found that family history is a good predictor of being a mutation carrier. Five pathogenic BRCA1 mutations and one pathogenic BRCA2 mutation were detected in 85 index cases. © 2011 Springer Science+Business Media B.V.
PubMed | Payvand Clinical and Specialty Laboratory, Islamic Azad University at Tehran Medical, MSc in Molecular Oncology and Kawsar Human Genetics Research Center
Type: Journal Article | Journal: Iranian journal of cancer prevention | Year: 2015
Chronic myelogenous leukemia (CML) is a kind of hematopoietic stem-cell cancer. A significant number of CML patients who do not achieve an acceptable response to therapy, show acquired resistance against Imatinib. One of the most considerable causes of resistance against Imatinib as the first line of therapy, are BCR-ABL kinase domain mutations.One of the most considerable causes of resistance against Imatinib as the first line of therapy, are BCR-ABL kinase domain mutations.The study was performed on 39 CML patients with Imatinib resistance. Basic hematologic parameters in blood samples were checked to identify hematologic response. To identify molecular response, BCR-ABL/ABL ratio was assessed by Real-time PCR. The ABL kinase domain amplification was performed by PCR. Restriction fragment length polymorphism (RFLP) was performed to detect four common mutations (T315I, Y253H, E255K and M351T). Finally the results were approved by direct sequencing.In this study, the Y253H mutation, detected by RFLP method and confirmed by direct sequencing, was the prevalent ABL kinase domain mutation in these 39 CML patients. The G250E, V379I and L384M mutations were found in three different cases with failure molecular response. CML patients with these four ABL kinase domain mutations cannot achieve major molecular response (MMR). In addition, complete hematologic response (CHR) was observed only in the V379I mutated case and not in other mutated patients.Identification of ABL kinase domain mutations may be used as a proper and useful method for improving therapeutic strategies, avoiding delay in treatment and excessive expenditure in CML patients with Imatinib resistance.
PubMed | Royan Institute for Stem Cell Biology and Technology, Tehran University of Medical Sciences, Kawsar Human Genetics Research Center, Pasteur Institute of Iran and 2 more.
Type: Journal Article | Journal: Metabolic brain disease | Year: 2016
Maple Syrup Urine Disease (MSUD) is a rare autosomal recessive disorder of branched-chain amino acid (BCAA) metabolism. The disease is mainly caused by mutations either in the BCKDHA, BCKDHB, DBT or DLD genes encoding components of the E1, E1, E2 and E3 subunits of branched-chain -keto acid dehydrogenase complex (BCKDC), respectively. BCKDC is a mitochondrial enzyme which is responsible for the normal breakdown of BCAA. The rate of consanguineous marriage in Iran is 38.6%, so the prevalence of autosomal recessive disorders is higher in comparison to other countries. Consanguinity increases the chance of the presence of pathogenic mutations in a homoallelic state. This phenomenon has made homozygosity mapping a powerful tool for finding the probable causative gene in heterogeneous disorders like IEM (Inborn Errors of Metabolism). In this study, two sets of multiplex polymorphic STR (Short Tandem Repeat) markers linked to the above-mentioned genes were selected to identify the probable pathogenic gene in the studied families. The families who showed a homozygous haplotype for the STR markers of the BCKDHB gene were subsequently sequenced. Four novel mutations including c.633+1G>A, c.988G>A, c.833_834insCAC, and a homozygous deletion of whole exon 3 c. (274+1_275-1) _(343+1_344-1), as well as one recently reported (c. 508G>T) mutation have been identified. Interestingly, three families shared a common haplotype structure along with the c. 508G>T mutation. Also, four other families revealed another similar haplotype with c.988G>A mutation. Founder effect can be a suggestive mechanism for the disease. Additionally, structural models of MSUD mutations have been performed to predict the pathogenesis of the newly identified variants.
Sharafi Farzad M.,Kawsar Human Genetics Research Center |
Tomas C.,Copenhagen University |
Borsting C.,Copenhagen University |
Zeinali Z.,Kawsar Human Genetics Research Center |
And 4 more authors.
Forensic Science International: Genetics | Year: 2013
A total number of 149 individuals from Iran (Persians, Lurs and Kurds) were analyzed for 49 autosomal SNPs using PCR, SBE and capillary electrophoresis. No deviation from Hardy-Weinberg expectations was observed. One SNP pair (rs1015250-rs251934) showed significant linkage disequilibrium in Kurds. However, this was most likely due to chance. High intrapopulation variability and no significant population structure were observed among the three ethnic groups from Iran. Pairwise FST values obtained from the mean numbers of pairwise differences between SNP profiles were calculated for Persians, Lurs, Kurds and eighteen other worldwide populations. For each of the three Iranian ethnic groups, the lowest FST values calculated between an Iranian and non-Iranian populations were observed between Iranians and populations in Iraq and Turkey. The three Iranian ethnic groups grouped together with other West Asian populations in the MDS plot drawn from the FST values. Statistical parameters of forensic interest calculated for the Iranian ethnic groups showed values of the same order of magnitudes as those obtained for Asians. The mean match probability calculated for the 49 SNPs ranged from 1.7 × 10-18 for Kurds to 1.3 × 10-19 for Persians. Despite the low level of genetic structure observed among Persians, Lurs and Kurds, a single autosomal SNP database should be used with care when extending its forensic application to other Iranian ethnic groups. © 2013 Elsevier Ireland Ltd. All rights reserved.
Keshavarzi F.,Islamic Azad University at Sanandaj Branch |
Noughani A.E.,Kawsar Human Genetics Research Center |
Ayoubian M.H.,Islamic Azad University at Sanandaj Branch |
Zeinali S.,Kawsar Human Genetics Research Center
Iranian Journal of Public Health | Year: 2011
Background: BRCA1 and BRCA2 genes have been recognized to be responsible for 20-30% of hereditary breast cancers and approximately 50% of familial breast and ovarian cancers. Therefore, the demand for BRCA1 and BRCA2 mutation screening is rapidly increasing as their identification will affect medical management of people at increased risk. Because of high costs involved in analysis of BRCA1 and 2 genes, contribution of different mutation types in BRCA1 and 2 and not knowing who should be tested has hampered wide spread use of molecular testing of high -risk families. There is a need to identify the genes and types of mutations involved in breast or ovarian cancers at different age of onsets and polymorphism and polymorphic variations in our population. Methods: Twenty-seven patients with either early onset breast cancer (at age≤ 35 years) or a personal and/or family history of breast or ovarian cancer and 50 control subjects participated in this study. After collecting blood samples and extracting DNA, BRCA1 and BRCA2 genes were fully sequenced. Results: Thirteen missense substitutions in BRCA1 and BRCA2 (9 and 4, respectively) were revealed. Two nucleotide substitutions were novel (Gly1140Ser in BRCA1 and Glu1391Gly in BRCA2). The Glu1038Pro and Gly1140Ser were found in large series of breast and ovarian cancer and matched controls. Conclusion: Some nucleotide substitutions were seen only in single families and other in several. In other cases, mutations were seen in both BRCA1 and BRCA2 genes. Clinical significance of these mutations was evaluated comparing with normal controls.
Poulsen L.,Copenhagen University |
Farzad M.S.,Kawsar Human Genetics Research Center |
Borsting C.,Copenhagen University |
Tomas C.,Copenhagen University |
And 2 more authors.
Forensic Science International: Genetics | Year: 2015
A total of 255 individuals (Persians, Lurs, Kurds and Azeris) from Iran were typed for three sets of forensic genetic markers with the NGM SElect™, DIPplex® and Argus X-12 kits. Statistically significant deviations (P ≤ 0.002) from Hardy-Weinberg expectations were observed for the insertion-deletion markers HLD97 and HLD93 after Holm-Šidák correction. Statistically significant (P < 0.05) levels of linkage disequilibrium were observed between markers within two of the four studied X-chromosomal linkage groups. AMOVA analyses of the three sets of markers did not show population structure when the individuals were grouped according to their ethnic group. The Iranian population grouped closely to populations living geographically near to Iran based on pairwise Fst distances. The matching probabilities ranged from 1 in 3.2 × 10males by using haplotype frequencies of four X-chromosomal haplogroups to 1 in 3.4 × 10individuals for the 16 autosomal STRs. © 2015 Published by Elsevier Ireland Ltd.
PubMed | Kawsar Human Genetics Research Center, Tehran University of Medical Sciences, Pasteur Institute of Iran and Shahid Beheshti University
Type: Journal Article | Journal: Journal of molecular neuroscience : MN | Year: 2016
Calpainopathy is an autosomal recessive form of limb girdle muscular dystrophies which is caused by mutation in CAPN3 gene. In the present study, co-segregation of this disorder was analyzed with four short tandem repeat markers linked to the CAPN3 gene. Three apparently unrelated Iranian families with same ethnicity were investigated. Haplotype analysis and sequencing of the CAPN3 gene were performed. DNA sample from one of the patients was simultaneously sent for next-generation sequencing. DNA sequencing identified two mutations. It was seen as a homozygous c.2105C>T in exon 19 in one family, a homozygous novel mutation c.380G>A in exon 3 in another family, and a compound heterozygote form of these two mutations in the third family. Next-generation sequencing also confirmed our results. It was expected that, due to the rare nature of limb girdle muscular dystrophies, affected individuals from the same ethnic group share similar mutations. Haplotype analysis showed two different homozygote patterns in two families, yet a compound heterozygote pattern in the third family as seen in the mutation analysis. This study shows that haplotype analysis would help in determining presence of different founders.
PubMed | Copenhagen University and Kawsar Human Genetics Research Center
Type: | Journal: Forensic science international. Genetics | Year: 2015
A total of 255 individuals (Persians, Lurs, Kurds and Azeris) from Iran were typed for three sets of forensic genetic markers with the NGM SElect, DIPplex() and Argus X-12 kits. Statistically significant deviations (P0.002) from Hardy-Weinberg expectations were observed for the insertion-deletion markers HLD97 and HLD93 after Holm-idk correction. Statistically significant (P<0.05) levels of linkage disequilibrium were observed between markers within two of the four studied X-chromosomal linkage groups. AMOVA analyses of the three sets of markers did not show population structure when the individuals were grouped according to their ethnic group. The Iranian population grouped closely to populations living geographically near to Iran based on pairwise FST distances. The matching probabilities ranged from 1 in 3.210(7) males by using haplotype frequencies of four X-chromosomal haplogroups to 1 in 3.410(21) individuals for the 16 autosomal STRs.
PubMed | High Institute for Research and Education in Transfusion Medicine, Pasteur Institute of Iran and Kawsar Human Genetics Research Center
Type: Journal Article | Journal: International journal of hematology-oncology and stem cell research | Year: 2016
Thalassemia syndromes are the most prevalent single gene disorders in Iran. This study aimed to evaluate the effect of different types of beta-globin gene mutations, co-inheritance of alpha-globin gene mutations and/or Xmn1 SNP on disease phenotype in a large cohort of Iranian patients.In total, 433 patients were clinically classified into -thalassemia major (TM) or intermedia (TI). Multiplex PCR, ARMS-PCR, RFLP-PCR and DNA sequencing were performed to identify both - and -globin gene mutations and Xmn1 polymorphism as well. All data were compared and analyzed by SPSS software in TM and TI groups, consequently.A total of 39 different -globin mutations were identified. Among them, the most common were IVS IInt1 (40.33%) followed by IVS Int5 (9.56%), C30 (7.22%) and Fr8-9(7%). All patients were subjected to evaluate common -globin gene deletions. The patients inherited concomitant mutations of - and -globin, showed no clinical modifications compared with those who had only -globin mutation. The TI patients showed a significant increase in frequency of both heterozygous and homozygous form of the Xmn1 polymorphism. It was also found that (0)/(0) genotype patients, inherited the Xmn1 polymorphism required lesser blood transfusion.No significant differences were observed, on the severity of disease, between patients inherited defective - and -globin genes and ones with just -globin gene mutation. Taking the results of this research into account, Xmn1 polymorphism can be considered as an important genetic factor modulating the severity of disease.