Seyedeh Sedigheh Abedini

Publications of Seyedeh Sedigheh Abedini

• The modifying effect of Xmn1-HBG2 on thalassemic phenotype is associated with its linked elements in the beta globin locus control region, including the palindromic site at 5'HS4.

  Authors: Maryam Neishabury, Shahbaz Zamani, Azita Azarkeivan, Seyedeh Sedigheh Abedini, Hossein Darvish, Fahimeh Zamani, Hossein Najmabadi

  Blood cells, molecules & diseases. 01/2012; 48(1):1-5.

  The core sequence of 5'HS4-beta globin locus control region and Xmn1-HBG2 site were analyzed and compared among 86 thalassemia patients with homozygous or compound heterozygous beta globin geneThe core sequence of 5'HS4-beta globin locus control region and Xmn1-HBG2 site were analyzed and compared among 86 thalassemia patients with homozygous or compound heterozygous beta globin gene mutations and 101 normal individuals. Frequency of the G allele in the polymorphic palindromic sequence of 5'HS4 (TGGGG A/G CCCCA) and positive Xmn1-HBG2 profile was significantly higher in thalassemia patients compared to the normal population. Linkage disequilibrium was observed between the G allele and positive Xmn1-HBG2 profile in patient population. Furthermore, dominance of IVSII-1 in the mutation spectrum of the patients enabled us to identify linkage disequilibrium relationships between IVSII-1, positive Xmn1-HBG2 and the G allele at 5'HS4. The frequency of milder clinical phenotype was significantly higher in patients with GG/++ than cases with AA/-- genotypic pattern in 5'HS4/Xmn1-HBG2 loci. These data together with biochemical evidence suggesting a role for the A/G polymorphism at 5'HS4 palindromic site on modifying chromatin structure and in the absence of any evidence from functional studies relating the Xmn1-HBG2 site to the increased gamma chain expression, suggest that the phenotype modifying role long time assigned to Xmn1-HBG2 is possibly played by more functionally potent elements linked to it in LCR.

• Deep sequencing reveals 50 novel genes for recessive cognitive disorders.

  Authors: Hossein Najmabadi, Hao Hu, Masoud Garshasbi, Tomasz Zemojtel, Seyedeh Sedigheh Abedini, Wei Chen, Masoumeh Hosseini, Farkhondeh Behjati, Stefan Haas, Payman Jamali [......] Mohammad Javad Soltani Banavandi, Julia Hoffer, Masoumeh Falah, Luciana Musante, Vera Kalscheuer, Reinhard Ullmann, Andreas Walter Kuss, Andreas Tzschach, Kimia Kahrizi, H Hilger Ropers

  Nature. 09/2011; 478(7367):57-63.

  Common diseases are often complex because they are genetically heterogeneous, with many different genetic defects giving rise to clinically indistinguishable phenotypes. This has been amplyCommon diseases are often complex because they are genetically heterogeneous, with many different genetic defects giving rise to clinically indistinguishable phenotypes. This has been amply documented for early-onset cognitive impairment, or intellectual disability, one of the most complex disorders known and a very important health care problem worldwide. More than 90 different gene defects have been identified for X-chromosome-linked intellectual disability alone, but research into the more frequent autosomal forms of intellectual disability is still in its infancy. To expedite the molecular elucidation of autosomal-recessive intellectual disability, we have now performed homozygosity mapping, exon enrichment and next-generation sequencing in 136 consanguineous families with autosomal-recessive intellectual disability from Iran and elsewhere. This study, the largest published so far, has revealed additional mutations in 23 genes previously implicated in intellectual disability or related neurological disorders, as well as single, probably disease-causing variants in 50 novel candidate genes. Proteins encoded by several of these genes interact directly with products of known intellectual disability genes, and many are involved in fundamental cellular processes such as transcription and translation, cell-cycle control, energy metabolism and fatty-acid synthesis, which seem to be pivotal for normal brain development and function.

• Mutation of the conserved polyadenosine RNA binding protein, ZC3H14/dNab2, impairs neural function in Drosophila and humans.

  Authors: Changhui Pak, Masoud Garshasbi, Kimia Kahrizi, Christina Gross, Luciano H Apponi, John J Noto, Seth M Kelly, Sara W Leung, Andreas Tzschach, Farkhondeh Behjati [......] Kathryn R Williams, Sharon Burdick, Yue Feng, Subhabrata Sanyal, Gary J Bassell, Hans-Hilger Ropers, Hossein Najmabadi, Anita H Corbett, Kenneth H Moberg, Andreas W Kuss

  Proceedings of the National Academy of Sciences of the United States of America. 07/2011; 108(30):12390-5.

  Here we report a human intellectual disability disease locus on chromosome 14q31.3 corresponding to mutation of the ZC3H14 gene that encodes a conserved polyadenosine RNA binding protein. We identifyHere we report a human intellectual disability disease locus on chromosome 14q31.3 corresponding to mutation of the ZC3H14 gene that encodes a conserved polyadenosine RNA binding protein. We identify ZC3H14 mRNA transcripts in the human central nervous system, and we find that rodent ZC3H14 protein is expressed in hippocampal neurons and colocalizes with poly(A) RNA in neuronal cell bodies. A Drosophila melanogaster model of this disease created by mutation of the gene encoding the ZC3H14 ortholog dNab2, which also binds polyadenosine RNA, reveals that dNab2 is essential for development and required in neurons for normal locomotion and flight. Biochemical and genetic data indicate that dNab2 restricts bulk poly(A) tail length in vivo, suggesting that this function may underlie its role in development and disease. These studies reveal a conserved requirement for ZC3H14/dNab2 in the metazoan nervous system and identify a poly(A) RNA binding protein associated with a human brain disorder.

• Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss.

  Authors: Niloofar Bazazzadegan, Abraham M Sheffield, Masoomeh Sobhani, Kimia Kahrizi, Nicole C Meyer, Guy Van Camp, Nele Hilgert, Seyedeh Sedigheh Abedini, Farkhondeh Habibi, Ahmad Daneshi, Carla Nishimura, Matthew R Avenarius, Mohammad Farhadi, Richard J H Smith, Hossein Najmabadi

  American journal of medical genetics. Part A. 05/2011; 155A(5):1202-11.

  Mutations in GJB2, encoding connexin 26 (Cx26), cause both autosomal dominant and autosomal recessive nonsyndromic hearing loss (ARNSHL) at the DFNA3 and DFNB1 loci, respectively. Most of the overMutations in GJB2, encoding connexin 26 (Cx26), cause both autosomal dominant and autosomal recessive nonsyndromic hearing loss (ARNSHL) at the DFNA3 and DFNB1 loci, respectively. Most of the over 100 described GJB2 mutations cause ARNSHL. Only a minority has been associated with autosomal dominant hearing loss. In this study, we present two families with autosomal dominant nonsyndromic hearing loss caused by a novel mutation in GJB2 (p.Asp46Asn). Both families were ascertained from the same village in northern Iran consistent with a founder effect. This finding implicates the D46N missense mutation in Cx26 as a common cause of deafness in this part of Iran mandating mutation screening of GJB2 for D46N in all persons with hearing loss who originate from this geographic region.

• Analyzing 5'HS3 and 5'HS4 LCR core regions and NF-E2 in Iranian thalassemia intermedia patients with normal or carrier status for beta-globin mutations.

  Authors: Maryam Neishabury, Azita Azarkeivan, Christian Oberkanins, Seyedeh Sedigheh Abedini, Shahbaz Zamani, Hossein Najmabadi

  Blood cells, molecules & diseases. 01/2011; 46(3):201-5.

  Our data on 114 Iranian individuals with thalassemia intermedia phenotype revealed homozygous or compound heterozygous beta-globin mutations to be the predominant disease factor in 86.2% of cases.Our data on 114 Iranian individuals with thalassemia intermedia phenotype revealed homozygous or compound heterozygous beta-globin mutations to be the predominant disease factor in 86.2% of cases. However, 8.2% of these individuals were found to be heterozygous or wild type for beta-globin mutations. In search for determinants outside of the beta-globin gene, which could be responsible for the unexpected thalassemia intermedia phenotype in these subjects, we screened the alpha-globin genes, the 5'HS3 and 5'HS4 regions of the beta-globin LCR, and the NF-E2 transcription factor for sequence variations in selected individuals. The -3.7 deletion was the only alpha-globin mutation detected, and no alterations were found in 5'HS3 and NF-E2. Sequence analysis of the 5'HS4 LCR core region identified three known SNPs in a single patient, who required irregular blood transfusions. The A/G polymorphism in the 5'HS4 palindromic region was also observed to be variable. Family studies were carried out on a female G/G homozygous patient, who received irregular blood transfusions. Her father, who had the same heterozygous IVSII-1 beta-globin mutation but the A/G genotype at the 5'HS4 palindromic site, presented with mild anemia and no requirement for blood transfusions. This suggests an impact of SNPs in the 5'HS4 LCR core region on the thalassemia phenotype and offers an interesting subject for further investigations in the Iranian population.

• Next generation sequencing in a family with autosomal recessive Kahrizi syndrome (OMIM 612713) reveals a homozygous frameshift mutation in SRD5A3.

  Authors: Kimia Kahrizi, Cougar Hao Hu, Masoud Garshasbi, Seyedeh Sedigheh Abedini, Shirin Ghadami, Roxana Kariminejad, Reinhard Ullmann, Wei Chen, H-Hilger Ropers, Andreas W Kuss, Hossein Najmabadi, Andreas Tzschach

  European journal of human genetics : EJHG. 01/2011; 19(1):115-7.

  As part of a large-scale, systematic effort to unravel the molecular causes of autosomal recessive mental retardation, we have previously described a novel syndrome consisting of mental retardation,As part of a large-scale, systematic effort to unravel the molecular causes of autosomal recessive mental retardation, we have previously described a novel syndrome consisting of mental retardation, coloboma, cataract and kyphosis (Kahrizi syndrome, OMIM 612713) and mapped the underlying gene to a 10.4-Mb interval near the centromere on chromosome 4. By combining array-based exon enrichment and next generation sequencing, we have now identified a homozygous frameshift mutation (c.203dupC; p.Phe69LeufsX2) in the gene for steroid 5α-reductase type 3 (SRD5A3) as the disease-causing change in this interval. Recent evidence indicates that this enzyme is required for the conversion of polyprenol to dolichol, a step that is essential for N-linked protein glycosylation. Independently, another group has recently observed SRD5A3 mutations in several families with a type 1 congenital disorder of glycosylation (CDG type Ix, OMIM 212067), mental retardation, cerebellar ataxia and eye disorders. Our results show that Kahrizi syndrome and this CDG Ix subtype are allelic disorders, and they illustrate the potential of next-generation sequencing strategies for the elucidation of single gene defects.

• Autosomal recessive mental retardation: homozygosity mapping identifies 27 single linkage intervals, at least 14 novel loci and several mutation hotspots.

  Authors: Andreas Walter Kuss, Masoud Garshasbi, Kimia Kahrizi, Andreas Tzschach, Farkhondeh Behjati, Hossein Darvish, Lia Abbasi-Moheb, Lucia Puettmann, Agnes Zecha, Robert Weissmann [......] Valeh Hadavi, Gholamreza Bahrami-Monajemi, Mahboubeh Kasiri, Masoumeh Falah, Pooneh Nikuei, Atefeh Dehghan, Masoumeh Sobhani, Payman Jamali, Hans Hilger Ropers, Hossein Najmabadi

  Human genetics. 11/2010; 129(2):141-8.

  Mental retardation (MR) has a worldwide prevalence of around 2% and is a frequent cause of severe disability. Significant excess of MR in the progeny of consanguineous matings as well as functionalMental retardation (MR) has a worldwide prevalence of around 2% and is a frequent cause of severe disability. Significant excess of MR in the progeny of consanguineous matings as well as functional considerations suggest that autosomal recessive forms of MR (ARMR) must be relatively common. To shed more light on the causes of autosomal recessive MR (ARMR), we have set out in 2003 to perform systematic clinical studies and autozygosity mapping in large consanguineous Iranian families with non-syndromic ARMR (NS-ARMR). As previously reported (Najmabadi et al. in Hum Genet 121:43-48, 2007), this led us to the identification of 12 novel ARMR loci, 8 of which had a significant LOD score (OMIM: MRT5-12). In the meantime, we and others have found causative gene defects in two of these intervals. Moreover, as reported here, tripling the size of our cohort has enabled us to identify 27 additional unrelated families with NS-ARMR and single-linkage intervals; 14 of these define novel loci for non-syndromic ARMR. Altogether, 13 out of 39 single linkage intervals observed in our cohort were found to cluster at 6 different loci on chromosomes, i.e., 1p34, 4q27, 5p15, 9q34, 11p11-q13 and 19q13, respectively. Five of these clusters consist of two significantly overlapping linkage intervals, and on chr 1p34, three single linkage intervals coincide, including the previously described MRT12 locus. The probability for this distribution to be due to chance is only 1.14 × 10(-5), as shown by Monte Carlo simulation. Thus, in contrast to our previous conclusions, these novel data indicate that common molecular causes of NS-ARMR do exist, and in the Iranian population, the most frequent ones may well account for several percent of the patients. These findings will be instrumental in the identification of the underlying genes.

• Fragile X Syndrome Screening of Families with Consanguineous and Non-consanguineous Parents in the Iranian Population.

  Authors: Ali Reza Pouya, Seyedeh Sedigheh Abedini, Neda Mansoorian, Farkhondeh Behjati, Nooshin Nikzat, Marzieh Mohseni, Sahar Esmaeeli Nieh, Lia Abbasi, Hossein Darvish, Gholamreza Bahrami Monajemi, Susan Banihashemi, Kimia Kahrizi, Hans-Hilger Ropers, Hossein Najmabadi

  European journal of medical genetics. 05/2009;

  Fragile X syndrome is the most common form of inherited mental retardation (MR). It is caused by the expansion of CGG triplet repeats in the fragile X mental retardation 1 (FMR1) gene. In mentallyFragile X syndrome is the most common form of inherited mental retardation (MR). It is caused by the expansion of CGG triplet repeats in the fragile X mental retardation 1 (FMR1) gene. In mentally retarded males, the frequency of fragile X syndrome is approximately 2 to 3 percent, but little is known about its proportion in mentally retarded patients from countries where parental consanguinity is common. The objective of this study was to estimate the frequency of fragile X syndrome (FXS) in mentally retarded patients from Iran. We examined a total of 508 families with MR that had been referred to the Genetics Research Center (GRC) in Tehran of which 467 families had at least two mentally retarded children. In 384 families, the parents were related and in 124 they were not related of which most of them had putative or established X-linked inheritance pattern. Full FMR1 mutations were found in 32 of the 508 families studied (6.3%), in 19 out of 124 families with apparently unrelated parents (15.3%), and in 13 of the 384 consanguineous families (3.4%). Thus, in Iran, the relative frequency of FXS seems to be high, and in patients with unrelated parents is much higher. We also show that even in families with consanguineous parents, FXS has to be ruled out before assuming that familial MR is due to autosomal recessive gene defects. Molecular studies are in progress to explain the high proportion of FMR1 mutations in mentally retarded offspring of unrelated Iranian parents.

• A defect in the ionotropic glutamate receptor 6 gene (GRIK2) is associated with autosomal recessive mental retardation.

  Authors: Mohammad Mahdi Motazacker, Benjamin Rainer Rost, Tim Hucho, Masoud Garshasbi, Kimia Kahrizi, Reinhard Ullmann, Seyedeh Sedigheh Abedini, Sahar Esmaeeli Nieh, Saeid Hosseini Amini, Chandan Goswami, Andreas Tzschach, Lars Riff Jensen, Dietmar Schmitz, Hans-Hilger Ropers, Hossein Najmabadi, Andreas Walter Kuss

  American journal of human genetics. 11/2007; 81(4):792-8.

  Nonsyndromic mental retardation is one of the most important unresolved problems in genetic health care. Autosomal forms are far more common than X-linked forms, but, in contrast to the latter, theyNonsyndromic mental retardation is one of the most important unresolved problems in genetic health care. Autosomal forms are far more common than X-linked forms, but, in contrast to the latter, they are still largely unexplored. Here, we report a complex mutation in the ionotropic glutamate receptor 6 gene (GRIK2, also called "GLUR6") that cosegregates with moderate-to-severe nonsyndromic autosomal recessive mental retardation in a large, consanguineous Iranian family. The predicted gene product lacks the first ligand-binding domain, the adjacent transmembrane domain, and the putative pore loop, suggesting a complete loss of function of the GLU(K6) protein, which is supported by electrophysiological data. This finding provides the first proof that GLU(K6) is indispensable for higher brain functions in humans, and future studies of this and other ionotropic kainate receptors will shed more light on the pathophysiology of mental retardation.

• Homozygosity mapping in consanguineous families reveals extreme heterogeneity of non-syndromic autosomal recessive mental retardation and identifies 8 novel gene loci.

  Authors: Hossein Najmabadi, Mohammad Mahdi Motazacker, Masoud Garshasbi, Kimia Kahrizi, Andreas Tzschach, Wei Chen, Farkhondeh Behjati, Valeh Hadavi, Sahar Esmaeeli Nieh, Seyedeh Sedigheh Abedini [......] Saghar Ghasemi Firouzabadi, Payman Jamali, Masoumeh Falah, Seyed Morteza Seifati, Annette Grüters, Steffen Lenzner, Lars R Jensen, Franz Rüschendorf, Andreas W Kuss, H Hilger Ropers

  Human genetics. 04/2007; 121(1):43-8.

  Autosomal recessive gene defects are arguably the most important, but least studied genetic causes of severe cognitive dysfunction. Homozygosity mapping in 78 consanguineous Iranian families withAutosomal recessive gene defects are arguably the most important, but least studied genetic causes of severe cognitive dysfunction. Homozygosity mapping in 78 consanguineous Iranian families with nonsyndromic autosomal recessive mental retardation (NS-ARMR) has enabled us to determine the chromosomal localization of at least 8 novel gene loci for this condition. Our data suggest that in the Iranian population NS-ARMR is very heterogeneous, and they argue against the existence of frequent gene defects that account for more than a few percent of the cases.

• SNP array-based homozygosity mapping reveals MCPH1 deletion in family with autosomal recessive mental retardation and mild microcephaly.

  Authors: Masoud Garshasbi, Mohammad Mahdi Motazacker, Kimia Kahrizi, Farkhondeh Behjati, Seyedeh Sedigheh Abedini, Sahar Esmaeeli Nieh, Saghar Ghasemi Firouzabadi, Christian Becker, Franz Rüschendorf, Peter Nürnberg, Andreas Tzschach, Reza Vazifehmand, Fikret Erdogan, Reinhard Ullmann, Steffen Lenzner, Andreas W Kuss, H Hilger Ropers, Hossein Najmabadi

  Human genetics. 03/2006; 118(6):708-15.

  Very little is known about the molecular basis of autosomal recessive MR (ARMR) because in developed countries, small family sizes preclude mapping and identification of the relevant gene defects. WeVery little is known about the molecular basis of autosomal recessive MR (ARMR) because in developed countries, small family sizes preclude mapping and identification of the relevant gene defects. We therefore chose to investigate genetic causes of ARMR in large consanguineous Iranian families. This study reports on a family with six mentally retarded members. Array-based homozygosity mapping and high-resolution microarray-based comparative genomic hybridization (array CGH) revealed a deletion of approximately 150-200 kb, encompassing the promoter and the first six exons of the MCPH1 gene, one out of four genes that have been previously implicated in ARMR with microcephaly. Reexamination of affected individuals revealed a high proportion of prematurely condensed chromosomes, which is a hallmark of this condition, but in spite of the severity of the mutation, all patients showed only borderline to mild microcephaly. Therefore the phenotypic spectrum of MCPH1 mutations may be wider than previously assumed, with ARMR being the only consistent clinical finding.

• Fragile X syndrome screening of families with consanguineous and non-consanguineous parents in the Iranian population

  Authors: Ali Reza Pouya, Seyedeh Sedigheh Abedini, Neda Mansoorian, Farkhondeh Behjati, Nooshin Nikzat, Marzieh Mohseni, Sahar Esmaeeli Nieh, Lia Abbasi Moheb, Hossein Darvish, Gholamreza Bahrami Monajemi, Susan Banihashemi, Kimia Kahrizi, Hans-Hilger Ropers, Hossein Najmabadi

  European Journal of Medical Genetics, v.52, 170-173 (2009).

  Fragile X syndrome is the most common form of inherited mental retardation (MR). It is caused by the expansion of CGG triplet repeats in the fragile X mental retardation 1 (FMR1) gene. In mentallyFragile X syndrome is the most common form of inherited mental retardation (MR). It is caused by the expansion of CGG triplet repeats in the fragile X mental retardation 1 (FMR1) gene. In mentally retarded males, the frequency of fragile X syndrome is approximately 2–3 percent, but little is known about its proportion in mentally retarded patients from countries where parental consanguinity is common. The objective of this study was to estimate the frequency of fragile X syndrome (FXS) in mentally retarded patients from Iran. We examined a total of 508 families with MR that had been referred to the Genetics Research Center (GRC) in Tehran of which 467 families had at least two mentally retarded children. In 384 families, the parents were related and in 124 they were not related of which most of them had putative or established X-linked inheritance pattern. Full FMR1 mutations were found in 32 of the 508 families studied (6.3%), in 19 out of 124 families with apparently unrelated parents (15.3%), and in 13 of the 384 consanguineous families (3.4%). Thus, in Iran, the relative frequency of FXS seems to be high, and in patients with unrelated parents is much higher. We also show that even in families with consanguineous parents, FXS has to be ruled out before assuming that familial MR is due to autosomal recessive gene defects. Molecular studies are in progress to explain the high proportion of FMR1 mutations in mentally retarded offspring of unrelated Iranian parents.