Andreas Walter Kuss

Publications of Andreas Walter Kuss

• 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.

• 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.

• Brachyphalangy, polydactyly and tibial aplasia/hypoplasia syndrome (OMIM 609945): case report and review of the literature.

  Authors: Yousef Shafeghati, Kimia Kahrizi, Hossein Najmabadi, Andreas Walter Kuss, Hans-Hilger Ropers, Andreas Tzschach

  European journal of pediatrics. 12/2010; 169(12):1535-9.

  Brachyphalangy, polydactyly and tibial aplasia/hypoplasia syndrome (OMIM 609945) is a rare congenital disorder. Only seven patients have been reported to date, and the etiology of this syndrome isBrachyphalangy, polydactyly and tibial aplasia/hypoplasia syndrome (OMIM 609945) is a rare congenital disorder. Only seven patients have been reported to date, and the etiology of this syndrome is unknown. Autosomal dominant inheritance with variable expression has been suggested based on the presence of minor features in some parents and the fact that neither parental consanguinity nor pairs of affected siblings were observed. We report on the first patient with this syndrome who was born to consanguineous parents. Neither the mother nor the father, who were first cousins, had clinical features suggestive of a manifestation of brachyphalangy, polydactyly and tibial aplasia/hypoplasia syndrome. The patient had no siblings, and the family history was unremarkable. Clinical problems included brachydactyly of hands and feet, splaying of fingers and toes, preaxial polydactyly of feet, bilateral tibial aplasia, shortened radius and ulna, and characteristic facial dysmorphic signs. The detailed description of this patient adds to our knowledge of the clinical manifestations of brachyphalangy, polydactyly and tibial aplasia/hypoplasia syndrome and will eventually also contribute to the elucidation of the underlying 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.

• 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.

• MicroRNAs in brain function and disease.

  Authors: Andreas Walter Kuss, Wei Chen

  Current neurology and neuroscience reports. 06/2008; 8(3):190-7.

  MicroRNAs (miRNAs), a class of small, non-protein-coding transcripts about 21 nucleotides long, have recently entered center stage in the study of posttranscriptional gene regulation. They are nowMicroRNAs (miRNAs), a class of small, non-protein-coding transcripts about 21 nucleotides long, have recently entered center stage in the study of posttranscriptional gene regulation. They are now thought to be involved in the control of about one third of all protein-coding genes and play a role in the majority of cellular processes that have been studied. We focus on the role of the miRNA pathway in brain development, function, and disease by highlighting recent observations with respect to miRNA-mediated gene regulation in neuronal differentiation, synaptic plasticity, and the circadian clock. We also discuss the implications of these findings with respect to the involvement of miRNAs in the etiopathology of brain disorders and pinpoint the emerging therapeutic potential of miRNAs for the treatment of human diseases.

• 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.

• MCT8 mutation analysis and identification of the first female with Allan-Herndon-Dudley syndrome due to loss of MCT8 expression.

  Authors: Suzanna Gerarda Maria Frints, Steffen Lenzner, Mareike Bauters, Lars Riff Jensen, Hilde Van Esch, Vincent des Portes, Ute Moog, Merryn Victor Erik Macville, Kees van Roozendaal, Constance Theresia Rimbertha Maria Schrander-Stumpel [......] Hans van Bokhoven, Jamel Chelly, Chérif Beldjord, Gillian Turner, Jozef Gecz, Claude Moraine, Martine Raynaud, Hans-Hilger Ropers, Guy Froyen, Andreas Walter Kuss

  European journal of human genetics : EJHG. 04/2008;

  Mutations in the thyroid monocarboxylate transporter 8 gene (MCT8/SLC16A2) have been reported to result in X-linked mental retardation (XLMR) in patients with clinical features of theMutations in the thyroid monocarboxylate transporter 8 gene (MCT8/SLC16A2) have been reported to result in X-linked mental retardation (XLMR) in patients with clinical features of the Allan-Herndon-Dudley syndrome (AHDS). We performed MCT8 mutation analysis including 13 XLMR families with LOD scores >2.0, 401 male MR sibships and 47 sporadic male patients with AHDS-like clinical features. One nonsense mutation (c.629insA) and two missense changes (c.1A>T and c.1673G>A) were identified. Consistent with previous reports on MCT8 missense changes, the patient with c.1673G>A showed elevated serum T3 level. The c.1A>T change in another patient affects a putative translation start codon, but the same change was present in his healthy brother. In addition normal serum T3 levels were present, suggesting that the c.1A>T (NM_006517) variation is not responsible for the MR phenotype but indicates that MCT8 translation likely starts with a methionine at position p.75. Moreover, we characterized a de novo translocation t(X;9)(q13.2;p24) in a female patient with full blown AHDS clinical features including elevated serum T3 levels. The MCT8 gene was disrupted at the X-breakpoint. A complete loss of MCT8 expression was observed in a fibroblast cell-line derived from this patient because of unfavorable nonrandom X-inactivation. Taken together, these data indicate that MCT8 mutations are not common in non-AHDS MR patients yet they support that elevated serum T3 levels can be indicative for AHDS and that AHDS clinical features can be present in female MCT8 mutation carriers whenever there is unfavorable nonrandom X-inactivation.European Journal of Human Genetics advance online publication, 9 April 2008; doi:10.1038/ejhg.2008.66.

• 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.

• X-linked mental retardation: a comprehensive molecular screen of 47 candidate genes from a 7.4 Mb interval in Xp11.

  Authors: Lars Riff Jensen, Steffen Lenzner, Bettina Moser, Kristine Freude, Andreas Tzschach, Chen Wei, Jean-Pierre Fryns, Jamel Chelly, Gillian Turner, Claude Moraine, Ben Hamel, Hans-Hilger Ropers, Andreas Walter Kuss

  European journal of human genetics : EJHG. 02/2007; 15(1):68-75.

  About 30% of the mutations causing nonsyndromic X-linked mental retardation (MRX) are thought to be located in Xp11 and in the pericentromeric region, with a particular clustering of gene defects inAbout 30% of the mutations causing nonsyndromic X-linked mental retardation (MRX) are thought to be located in Xp11 and in the pericentromeric region, with a particular clustering of gene defects in a 7.4 Mb interval flanked by the genes ELK1 and ALAS2. To search for these mutations, 47 brain-expressed candidate genes located in this interval have been screened for mutations in up to 22 mental retardation (MR) families linked to this region. In total, we have identified 57 sequence variants in exons and splice sites of 27 genes. Based on these data, four novel MR genes were identified, but most of the sequence variants observed during this study have not yet been described. The purpose of this article is to present a comprehensive overview of this work and its outcome. It describes all sequence variants detected in 548 exons and their flanking sequences, including disease-causing mutations as well as possibly relevant polymorphic and silent sequence changes. We show that many of the studied genes are unlikely to play a major role in MRX. This information will help to avoid duplication of efforts in the ongoing endeavor to unravel the molecular causes of MRX.