Masoud Garshasbi

Publications of Masoud Garshasbi

• Mutations in NSUN2 Cause Autosomal- Recessive Intellectual Disability.

  Authors: Lia Abbasi-Moheb, Sara Mertel, Melanie Gonsior, Leyla Nouri-Vahid, Kimia Kahrizi, Sebahattin Cirak, Dagmar Wieczorek, M Mahdi Motazacker, Sahar Esmaeeli-Nieh, Kirsten Cremer, Robert Weißmann, Andreas Tzschach, Masoud Garshasbi, Seyedeh S Abedini, Hossein Najmabadi, H Hilger Ropers, Stephan J Sigrist, Andreas W Kuss

  American journal of human genetics. 04/2012;

  With a prevalence between 1 and 3%, hereditary forms of intellectual disability (ID) are among the most important problems in health care. Particularly, autosomal-recessive forms of the disorder haveWith a prevalence between 1 and 3%, hereditary forms of intellectual disability (ID) are among the most important problems in health care. Particularly, autosomal-recessive forms of the disorder have a very heterogeneous molecular basis, and genes with an increased number of disease-causing mutations are not common. Here, we report on three different mutations (two nonsense mutations, c.679C>T [p.Gln227(∗)] and c.1114C>T [p.Gln372(∗)], as well as one splicing mutation, g.6622224A>C [p.Ile179Argfs(∗)192]) that cause a loss of the tRNA-methyltransferase-encoding NSUN2 main transcript in homozygotes. We identified the mutations by sequencing exons and exon-intron boundaries within the genomic region where the linkage intervals of three independent consanguineous families of Iranian and Kurdish origin overlapped with the previously described MRT5 locus. In order to gain further evidence concerning the effect of a loss of NSUN2 on memory and learning, we constructed a Drosophila model by deleting the NSUN2 ortholog, CG6133, and investigated the mutants by using molecular and behavioral approaches. When the Drosophila melanogaster NSUN2 ortholog was deleted, severe short-term-memory (STM) deficits were observed; STM could be rescued by re-expression of the wild-type protein in the nervous system. The humans homozygous for NSUN2 mutations showed an overlapping phenotype consisting of moderate to severe ID and facial dysmorphism (which includes a long face, characteristic eyebrows, a long nose, and a small chin), suggesting that mutations in this gene might even induce a syndromic form of ID. Moreover, our observations from the Drosophila model point toward an evolutionarily conserved role of RNA methylation in normal cognitive development.

• 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.

• ST3GAL3 mutations impair the development of higher cognitive functions.

  Authors: Hao Hu, Katinka Eggers, Wei Chen, Masoud Garshasbi, M Mahdi Motazacker, Klaus Wrogemann, Kimia Kahrizi, Andreas Tzschach, Masoumeh Hosseini, Ideh Bahman, Tim Hucho, Martina Mühlenhoff, Rita Gerardy-Schahn, Hossein Najmabadi, H Hilger Ropers, Andreas W Kuss

  American journal of human genetics. 09/2011; 89(3):407-14.

  The genetic variants leading to impairment of intellectual performance are highly diverse and are still poorly understood. ST3GAL3 encodes the Golgi enzyme β-galactoside-α2,3-sialyltransferase-IIIThe genetic variants leading to impairment of intellectual performance are highly diverse and are still poorly understood. ST3GAL3 encodes the Golgi enzyme β-galactoside-α2,3-sialyltransferase-III that in humans predominantly forms the sialyl Lewis a epitope on proteins. ST3GAL3 resides on chromosome 1 within the MRT4 locus previously identified to associate with nonsyndromic autosomal recessive intellectual disability. We searched for the disease-causing mutations in the MRT4 family and a second independent consanguineous Iranian family by using a combination of chromosome sorting and next-generation sequencing. Two different missense changes in ST3GAL3 cosegregate with the disease but were absent in more than 1000 control chromosomes. In cellular and biochemical test systems, these mutations were shown to cause ER retention of the Golgi enzyme and drastically impair ST3Gal-III functionality. Our data provide conclusive evidence that glycotopes formed by ST3Gal-III are prerequisite for attaining and/or maintaining higher cognitive functions.

• A novel nonsense mutation in TUSC3 is responsible for non-syndromic autosomal recessive mental retardation in a consanguineous Iranian family.

  Authors: Masoud Garshasbi, Kimia Kahrizi, Masoumeh Hosseini, Leila Nouri Vahid, Masoumeh Falah, Sahel Hemmati, Hao Hu, Andreas Tzschach, Hans Hilger Ropers, Hossein Najmabadi, Andreas Walter Kuss

  American journal of medical genetics. Part A. 08/2011; 155A(8):1976-80.

  The genetic basis of autosomal recessive mental retardation (ARMR) is extremely heterogeneous, and there is reason to suspect that the number of underlying gene defects may well go beyond 1,000. ToThe genetic basis of autosomal recessive mental retardation (ARMR) is extremely heterogeneous, and there is reason to suspect that the number of underlying gene defects may well go beyond 1,000. To date, however, only less than 10 genes have been implicated in non-specific/non-syndromic ARMR (NS-ARMR). As part of an ongoing systematic study aiming to identify further ARMR genes, we investigated a consanguineous family with three patients with NS-ARMR. By linkage analysis and subsequent mutation screening we identified a novel nonsense mutation (c.163C > T [p.Q55X]) in the second exon of the TUSC3 gene. This is the third MR causing defect in TUSC3 to be described and the second independent mutation in this gene in a cohort of more than 200 ARMR families from the Iranian population. This argues for a more prominent role of TUSC3 in the etiology of this genetically heterogeneous disorder as compared to most of the other so far identified ARMR genes.

• 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.

• Mutations in the alpha 1,2-mannosidase gene, MAN1B1, cause autosomal-recessive intellectual disability.

  Authors: Muhammad Arshad Rafiq, Andreas W Kuss, Lucia Puettmann, Abdul Noor, Annapoorani Ramiah, Ghazanfar Ali, Hao Hu, Nadir Ali Kerio, Yong Xiang, Masoud Garshasbi [......] Andreas Tzschach, Kimia Kahrizi, Khalid Mahmood, Farooq Naeem, Muhammad Ayub, Kelley W Moremen, John B Vincent, Hans Hilger Ropers, Muhammad Ansar, Hossein Najmabadi

  American journal of human genetics. 07/2011; 89(1):176-82.

  We have used genome-wide genotyping to identify an overlapping homozygosity-by-descent locus on chromosome 9q34.3 (MRT15) in four consanguineous families affected by nonsyndromic autosomal-recessiveWe have used genome-wide genotyping to identify an overlapping homozygosity-by-descent locus on chromosome 9q34.3 (MRT15) in four consanguineous families affected by nonsyndromic autosomal-recessive intellectual disability (NS-ARID) and one in which the patients show additional clinical features. Four of the families are from Pakistan, and one is from Iran. Using a combination of next-generation sequencing and Sanger sequencing, we have identified mutations in the gene MAN1B1, encoding a mannosyl oligosaccharide, alpha 1,2-mannosidase. In one Pakistani family, MR43, a homozygous nonsense mutation (RefSeq number NM_016219.3: c.1418G>A [p.Trp473*]), segregated with intellectual disability and additional dysmorphic features. We also identified the missense mutation c. 1189G>A (p.Glu397Lys; RefSeq number NM_016219.3), which segregates with NS-ARID in three families who come from the same village and probably have shared inheritance. In the Iranian family, the missense mutation c.1000C>T (p.Arg334Cys; RefSeq number NM_016219.3) also segregates with NS-ARID. Both missense mutations are at amino acid residues that are conserved across the animal kingdom, and they either reduce k(cat) by ∼1300-fold or disrupt stable protein expression in mammalian cells. MAN1B1 is one of the few NS-ARID genes with an elevated mutation frequency in patients with NS-ARID from different populations.

• Identification of a novel candidate gene for non-syndromic autosomal recessive intellectual disability: the WASH complex member SWIP.

  Authors: Fabienne Ropers, Emmanuel Derivery, Hao Hu, Masoud Garshasbi, Mohsen Karbasiyan, Martin Herold, Gudrun Nürnberg, Reinhard Ullmann, Alexis Gautreau, Karl Sperling, Raymonda Varon, Anna Rajab

  Human molecular genetics. 07/2011; 20(13):2585-90.

  High-throughput sequencing has greatly facilitated the elucidation of genetic disorders, but compared with X-linked and autosomal dominant diseases, the search for genetic defects underlyingHigh-throughput sequencing has greatly facilitated the elucidation of genetic disorders, but compared with X-linked and autosomal dominant diseases, the search for genetic defects underlying autosomal recessive diseases still lags behind. In a large consanguineous family with autosomal recessive intellectual disability (ARID), we have combined homozygosity mapping, targeted exon enrichment and high-throughput sequencing to identify the underlying gene defect. After appropriate single-nucleotide polymorphism filtering, only two molecular changes remained, including a non-synonymous sequence change in the SWIP [Strumpellin and WASH (Wiskott-Aldrich syndrome protein and scar homolog)-interacting protein] gene, a member of the recently discovered WASH complex, which is involved in actin polymerization and multiple endosomal transport processes. Based on high pathogenicity and evolutionary conservation scores as well as functional considerations, this gene defect was considered as causative for ID in this family. In line with this assumption, we could show that this mutation leads to significantly reduced SWIP levels and to destabilization of the entire WASH complex. Thus, our findings suggest that SWIP is a novel gene for ARID.

• 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.

• Cohen syndrome diagnosis using whole genome arrays.

  Authors: Nuria Rivera-Brugués, Beate Albrecht, Dagmar Wieczorek, Heinrich Schmidt, Thomas Keller, Ina Göhring, Arif B Ekici, Andreas Tzschach, Masoud Garshasbi, Kathlen Franke, Norman Klopp, H-Erich Wichmann, Thomas Meitinger, Tim M Strom, Maja Hempel

  Journal of medical genetics. 10/2010; 48(2):136-40.

  Cohen syndrome is a rare autosomal recessive disorder with a complex phenotype including psychomotor retardation, microcephaly, obesity with slender extremities, joint laxity, progressiveCohen syndrome is a rare autosomal recessive disorder with a complex phenotype including psychomotor retardation, microcephaly, obesity with slender extremities, joint laxity, progressive chorioretinal dystrophy/myopia, intermittent isolated neutropenia, a cheerful disposition, and characteristic facial features. The COH1 gene, which contains 62 exons, is so far the only gene known to be associated with Cohen syndrome. Point mutations, deletions and duplications have been described in this gene. Oligonucleotide arrays have reached a resolution which allows the detection of intragenic deletions and duplications, especially in large genes such as COH1. High density oligonucleotide array data from patients with unexplained mental retardation (n=1523) and normal controls (n=1612) were analysed for copy number variation (CNV) changes. Intragenic heterozygous deletions in the COH1 gene were detected in three patients but no such changes were detected in the controls. Subsequent sequencing of the COH1 gene revealed point mutations in the second allele in all three patients analysed. Genome-wide CNV screening with high density arrays provides a tool to detect intragenic deletions in the COH1 gene. This report presents an example of how microarrays can be used to identify autosomal recessive syndromes and to extend the phenotypic and mutational spectrum of recessive disorders.

• Cranioectodermal Dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene.

  Authors: Joanna Walczak-Sztulpa, Jonathan Eggenschwiler, Daniel Osborn, Desmond A Brown, Francesco Emma, Claus Klingenberg, Raoul C Hennekam, Giuliano Torre, Masoud Garshasbi, Andreas Tzschach, Malgorzata Szczepanska, Marian Krawczynski, Jacek Zachwieja, Danuta Zwolinska, Philip L Beales, Hans-Hilger Ropers, Anna Latos-Bielenska, Andreas W Kuss

  American journal of human genetics. 06/2010; 86(6):949-56.

  Cranioectodermal dysplasia (CED) is a disorder characterized by craniofacial, skeletal, and ectodermal abnormalities. Most cases reported to date are sporadic, but a few familial cases support anCranioectodermal dysplasia (CED) is a disorder characterized by craniofacial, skeletal, and ectodermal abnormalities. Most cases reported to date are sporadic, but a few familial cases support an autosomal-recessive inheritance pattern. Aiming at the elucidation of the genetic basis of CED, we collected 13 patients with CED symptoms from 12 independent families. In one family with consanguineous parents two siblings were affected, permitting linkage analysis and homozygosity mapping. This revealed a single region of homozygosity with a significant LOD score (3.57) on chromosome 3q21-3q24. By sequencing candidate genes from this interval we found a homozygous missense mutation in the IFT122 (WDR10) gene that cosegregated with the disease. Examination of IFT122 in our patient cohort revealed one additional homozygous missense change in the patient from a second consanguineous family. In addition, we found compound heterozygosity for a donor splice-site change and a missense change in one sporadic patient. All mutations were absent in 340 control chromosomes. Because IFT122 plays an important role in the assembly and maintenance of eukaryotic cilia, we investigated patient fibroblasts and found significantly reduced frequency and length of primary cilia as compared to controls. Furthermore, we transiently knocked down ift122 in zebrafish embryos and observed the typical phenotype found in other models of ciliopathies. Because not all of our patients harbored mutations in IFT122, CED seems to be genetically heterogeneous. Still, by identifying CED as a ciliary disorder, our study suggests that the causative mutations in the unresolved cases most likely affect primary cilia function too.

• Somatic mutation profiles of MSI and MSS colorectal cancer identified by whole exome next generation sequencing and bioinformatics analysis.

  Authors: Bernd Timmermann, Martin Kerick, Christina Roehr, Axel Fischer, Melanie Isau, Stefan T Boerno, Andrea Wunderlich, Christian Barmeyer, Petra Seemann, Jana Koenig, Michael Lappe, Andreas W Kuss, Masoud Garshasbi, Lars Bertram, Kathrin Trappe, Martin Werber, Bernhard G Herrmann, Kurt Zatloukal, Hans Lehrach, Michal R Schweiger

  PloS one. 01/2010; 5(12):e15661.

  Colorectal cancer (CRC) is with approximately 1 million cases the third most common cancer worldwide. Extensive research is ongoing to decipher the underlying genetic patterns with the hope toColorectal cancer (CRC) is with approximately 1 million cases the third most common cancer worldwide. Extensive research is ongoing to decipher the underlying genetic patterns with the hope to improve early cancer diagnosis and treatment. In this direction, the recent progress in next generation sequencing technologies has revolutionized the field of cancer genomics. However, one caveat of these studies remains the large amount of genetic variations identified and their interpretation. Here we present the first work on whole exome NGS of primary colon cancers. We performed 454 whole exome pyrosequencing of tumor as well as adjacent not affected normal colonic tissue from microsatellite stable (MSS) and microsatellite instable (MSI) colon cancer patients and identified more than 50,000 small nucleotide variations for each tissue. According to predictions based on MSS and MSI pathomechanisms we identified eight times more somatic non-synonymous variations in MSI cancers than in MSS and we were able to reproduce the result in four additional CRCs. Our bioinformatics filtering approach narrowed down the rate of most significant mutations to 359 for MSI and 45 for MSS CRCs with predicted altered protein functions. In both CRCs, MSI and MSS, we found somatic mutations in the intracellular kinase domain of bone morphogenetic protein receptor 1A, BMPR1A, a gene where so far germline mutations are associated with juvenile polyposis syndrome, and show that the mutations functionally impair the protein function. We conclude that with deep sequencing of tumor exomes one may be able to predict the microsatellite status of CRC and in addition identify potentially clinically relevant mutations.

• Establishment of a mouse model with misregulated chromosome condensation due to defective Mcph1 function.

  Authors: Marc Trimborn, Mahdi Ghani, Diego J Walther, Monika Dopatka, Véronique Dutrannoy, Andreas Busche, Franziska Meyer, Stefanie Nowak, Jean Nowak, Claus Zabel [......] Veronica Esquitino, Masoud Garshasbi, Andreas W Kuss, Hans-Hilger Ropers, Susanne Mueller, Charlotte Poehlmann, Ioannis Gavvovidis, Detlev Schindler, Karl Sperling, Heidemarie Neitzel

  PloS one. 01/2010; 5(2):e9242.

  Mutations in the human gene MCPH1 cause primary microcephaly associated with a unique cellular phenotype with premature chromosome condensation (PCC) in early G2 phase and delayed decondensationMutations in the human gene MCPH1 cause primary microcephaly associated with a unique cellular phenotype with premature chromosome condensation (PCC) in early G2 phase and delayed decondensation post-mitosis (PCC syndrome). The gene encodes the BRCT-domain containing protein microcephalin/BRIT1. Apart from its role in the regulation of chromosome condensation, the protein is involved in the cellular response to DNA damage. We report here on the first mouse model of impaired Mcph1-function. The model was established based on an embryonic stem cell line from BayGenomics (RR0608) containing a gene trap in intron 12 of the Mcph1 gene deleting the C-terminal BRCT-domain of the protein. Although residual wild type allele can be detected by quantitative real-time PCR cell cultures generated from mouse tissues bearing the homozygous gene trap mutation display the cellular phenotype of misregulated chromosome condensation that is characteristic for the human disorder, confirming defective Mcph1 function due to the gene trap mutation. While surprisingly the DNA damage response (formation of repair foci, chromosomal breakage, and G2/M checkpoint function after irradiation) appears to be largely normal in cell cultures derived from Mcph1(gt/gt) mice, the overall survival rates of the Mcph1(gt/gt) animals are significantly reduced compared to wild type and heterozygous mice. However, we could not detect clear signs of premature malignant disease development due to the perturbed Mcph1 function. Moreover, the animals show no obvious physical phenotype and no reduced fertility. Body and brain size are within the range of wild type controls. Gene expression on RNA and protein level did not reveal any specific pattern of differentially regulated genes. To the best of our knowledge this represents the first mammalian transgenic model displaying a defect in mitotic chromosome condensation and is also the first mouse model for impaired Mcph1-function.

• CA8 mutations cause a novel syndrome characterized by ataxia and mild mental retardation with predisposition to quadrupedal gait.

  Authors: Seval Türkmen, Gao Guo, Masoud Garshasbi, Katrin Hoffmann, Amjad J Alshalah, Claudia Mischung, Andreas Kuss, Nicholas Humphrey, Stefan Mundlos, Peter N Robinson

  PLoS genetics. 06/2009; 5(5):e1000487.

  We describe a consanguineous Iraqi family in which affected siblings had mild mental retardation and congenital ataxia characterized by quadrupedal gait. Genome-wide linkage analysis identified a 5.8We describe a consanguineous Iraqi family in which affected siblings had mild mental retardation and congenital ataxia characterized by quadrupedal gait. Genome-wide linkage analysis identified a 5.8 Mb interval on chromosome 8q with shared homozygosity among the affected persons. Sequencing of genes contained in the interval revealed a homozygous mutation, S100P, in carbonic anhydrase related protein 8 (CA8), which is highly expressed in cerebellar Purkinje cells and influences inositol triphosphate (ITP) binding to its receptor ITPR1 on the endoplasmatic reticulum and thereby modulates calcium signaling. We demonstrate that the mutation S100P is associated with proteasome-mediated degradation, and thus presumably represents a null mutation comparable to the Ca8 mutation underlying the previously described waddles mouse, which exhibits ataxia and appendicular dystonia. CA8 thus represents the third locus that has been associated with quadrupedal gait in humans, in addition to the VLDLR locus and a locus at chromosome 17p. Our findings underline the importance of ITP-mediated signaling in cerebellar function and provide suggestive evidence that congenital ataxia paired with cerebral dysfunction may, together with unknown contextual factors during development, predispose to quadrupedal gait in humans.

• Expanded mutational spectrum in cohen syndrome, tissue expression, and transcript variants of COH1.

  Authors: Wenke Seifert, Muriel Holder-Espinasse, Jirko Kühnisch, Kimia Kahrizi, Andreas Tzschach, Masoud Garshasbi, Hossein Najmabadi, Andreas Walter Kuss, Wolfram Kress, Geneviève Laureys, Bart Loeys, Eva Brilstra, Grazia M S Mancini, Hélène Dollfus, Karin Dahan, Kira Apse, Hans Christian Hennies, Denise Horn

  Human mutation. 12/2008;

  Cohen syndrome is characterised by mental retardation, postnatal microcephaly, facial dysmorphism, pigmentary retinopathy, myopia, and intermittent neutropenia. Mutations in COH1 (VPS13B) have beenCohen syndrome is characterised by mental retardation, postnatal microcephaly, facial dysmorphism, pigmentary retinopathy, myopia, and intermittent neutropenia. Mutations in COH1 (VPS13B) have been found in patients with Cohen syndrome from diverse ethnic origins. We have carried out mutation analysis in twelve novel patients with Cohen syndrome from nine families. In this series, we have identified 13 different mutations in COH1, twelve of these are novel including six frameshift mutations, four nonsense mutations, two splice site mutations, and a one-codon deletion. Since different transcripts of COH1 have been reported previously, we have analysed the expression patterns of COH1 splice variants. The transcript variant NM_152564 including exon 28b showed ubiquitous expression in all examined human tissues. In contrast, human brain and retina showed differential splicing of exon 28 (NM_017890). Moreover, analysis of mouse tissues revealed ubiquitous expression of Coh1 homologous to human NM_152564 in all examined tissues but no prevalent alternative splicing. (c) 2008 Wiley-Liss, Inc.

• An autosomal recessive syndrome of severe mental retardation, cataract, coloboma and kyphosis maps to the pericentromeric region of chromosome 4.

  Authors: Kimia Kahrizi, Hossein Najmabadi, Roxana Kariminejad, Payman Jamali, Mahdi Malekpour, Masoud Garshasbi, Hans-Hilger Ropers, Andreas Walter Kuss, Andreas Tzschach

  European journal of human genetics : EJHG. 10/2008;

  We report on three siblings with a novel mental retardation (MR) syndrome who were born to distantly related Iranian parents. The clinical problems comprised severe MR, cataracts with onset in lateWe report on three siblings with a novel mental retardation (MR) syndrome who were born to distantly related Iranian parents. The clinical problems comprised severe MR, cataracts with onset in late adolescence, kyphosis, contractures of large joints, bulbous nose with broad nasal bridge, and thick lips. Two patients also had uni- or bilateral iris coloboma. Linkage analysis revealed a single 10.4 Mb interval of homozygosity with significant LOD score in the pericentromeric region of chromosome 4 flanked by SNPs rs728293 (4p12) and rs1105434 (4q12). This interval contains more than 40 genes, none of which has been implicated in MR so far. The identification of the causative gene defect for this syndrome will provide new insights into the development of the brain and the eye.European Journal of Human Genetics advance online publication, 10 September 2008; doi:10.1038/ejhg.2008.159.

• A defect in the TUSC3 gene is associated with autosomal recessive mental retardation.

  Authors: Masoud Garshasbi, Valeh Hadavi, Haleh Habibi, Kimia Kahrizi, Roxana Kariminejad, Farkhondeh Behjati, Andreas Tzschach, Hossein Najmabadi, Hans-Hilger Ropers, Andreas Walter Kuss

  American journal of human genetics. 06/2008; 82(5):1158-64.

  Recent studies have shown that autosomal recessive mental retardation (ARMR) is extremely heterogeneous, and there is reason to believe that the number of underlying gene defects goes into theRecent studies have shown that autosomal recessive mental retardation (ARMR) is extremely heterogeneous, and there is reason to believe that the number of underlying gene defects goes into the thousands. To date, however, only four genes have been implicated in nonsyndromic ARMR (NS-ARMR): PRSS12 (neurotrypsin), CRBN (cereblon), CC2D1A, and GRIK2. As part of an ongoing systematic study aiming to identify ARMR genes, we investigated a large consanguineous family comprising seven patients with nonsyndromic ARMR in four sibships. Genome-wide SNP typing enabled us to map the relevant genetic defect to a 4.6 Mbp interval on chromosome 8. Haplotype analyses and copy-number studies led to the identification of a homozygous deletion partly removing TUSC3 (N33) in all patients. All obligate carriers of this family were heterozygous, but none of 192 unrelated healthy individuals from the same population carried this deletion. We excluded other disease-causing mutations in the coding regions of all genes within the linkage interval by sequencing; moreover, we verified the complete absence of a functional TUSC3 transcript in all patients through RT-PCR. TUSC3 is thought to encode a subunit of the endoplasmic reticulum-bound oligosaccharyltransferase complex that catalyzes a pivotal step in the protein N-glycosylation process. Our data suggest that in contrast to other genetic defects of glycosylation, inactivation of TUSC3 causes nonsyndromic MR, a conclusion that is supported by a separate report in this issue of AJHG. TUSC3 is only the fifth gene implicated in NS-ARMR and the first for which mutations have been reported in more than one family.

• Identification of a nonsense mutation in the very low-density lipoprotein receptor gene (VLDLR) in an Iranian family with dysequilibrium syndrome.

  Authors: Lia Abbasi Moheb, Andreas Tzschach, Masoud Garshasbi, Kimia Kahrizi, Hossein Darvish, Yaser Heshmati, Alireza Kordi, Hossein Najmabadi, Hans-Hilger Ropers, Andreas Walter Kuss

  European journal of human genetics : EJHG. 03/2008; 16(2):270-3.

  We have investigated a consanguineous Iranian family with eight patients who suffer from mental retardation, disturbed equilibrium, walking disability, strabismus and short stature. By autozygosityWe have investigated a consanguineous Iranian family with eight patients who suffer from mental retardation, disturbed equilibrium, walking disability, strabismus and short stature. By autozygosity mapping we identified one region with a significant LOD score on chromosome 9(p24.2-24.3). The interval contains the VLDLR gene, which codes for the very low-density lipoprotein receptor. This protein is part of the reelin signalling pathway, which is involved in neuroblast migration in the cerebral cortex and cerebellum. A homozygous deletion encompassing VLDLR has previously been found to cause a syndrome of cerebellar ataxia and mental retardation associated with cerebellar hypoplasia in the Hutterite population known as dysequilibrium syndrome (DES). The reported deletion however, contains an additional brain expressed gene of unknown function, whose involvement in the aetiology of the phenotype could so far not be excluded. We screened the coding region of VLDLR for mutations in our patients and found a homozygous c.1342C>T nucleotide substitution, which leads to a premature stop codon in exon 10. This is the first report of a mutation in patients with DES that affects VLDLR exclusively, confirming the central role of the very low-density lipoprotein receptor in the aetiology of this condition.

• 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.