Andreas W Kuss

Publications of Andreas W Kuss

• 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.

• 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.

• 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.

• A novel nonsense mutation in KDM5C/JARID1C gene causing intellectual disability, short stature and speech delay.

  Authors: Cíntia B Santos-Rebouças, Natalia Fintelman-Rodrigues, Lars R Jensen, Andreas W Kuss, Márcia G Ribeiro, Mário Campos, Jussara M Santos, Márcia M G Pimentel

  Neuroscience letters. 07/2011; 498(1):67-71.

  Mutations in the Jumonji AT-rich interactive domain 1C (JARID1C/SMCX/KDM5C) gene, located at Xp11.22, are emerging as frequent causes of X-linked intellectual disability (XLID). KDM5C encodes for aMutations in the Jumonji AT-rich interactive domain 1C (JARID1C/SMCX/KDM5C) gene, located at Xp11.22, are emerging as frequent causes of X-linked intellectual disability (XLID). KDM5C encodes for a member of an ARID protein family that harbors conserved DNA-binding motifs and acts as a histone H3 lysine 4 demethylase, suggesting a potential role in epigenetic regulation during development, cell growth and differentiation. In this study, we describe clinical and genetic findings of a Brazilian family co-segregating a novel nonsense mutation (c.2172C>A) in exon 15 of KDM5C gene with the intellectual disability phenotype. The transition resulted in replacement of the normal cysteine by a premature termination codon at position 724 of the protein (p.Cys724X), leading to reduced levels of KDM5C transcript probably due to nonsense mediated mRNA decay. The clinical phenotype of the proband, who has two affected brothers and a mild cognitively impaired mother, consisted of short stature, speech delay, hyperactivity, violent behavior and high palate, besides severe mental retardation. Our findings extend the number of KDM5C mutations implicated in XLID and highlight its promise for understanding neural function and unexplained cases of XLID.

• Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1.

  Authors: Lars R Jensen, Wei Chen, Bettina Moser, Bettina Lipkowitz, Christopher Schroeder, Luciana Musante, Andreas Tzschach, Vera M Kalscheuer, Ilaria Meloni, Martine Raynaud [......] Arjan P M de Brouwer, Anna Hackett, Sigrun van der Haar, Wolfram Henn, Jozef Gecz, Olaf Riess, Michael Bonin, Richard Reinhardt, Hans-Hilger Ropers, Andreas W Kuss

  European journal of human genetics : EJHG. 01/2011; 19(6):717-20.

  X-linked intellectual disability (XLID), also known as X-linked mental retardation, is a highly genetically heterogeneous condition for which mutations in >90 different genes have been identified. InX-linked intellectual disability (XLID), also known as X-linked mental retardation, is a highly genetically heterogeneous condition for which mutations in >90 different genes have been identified. In this study, we used a custom-made sequencing array based on the Affymetrix 50k platform for mutation screening in 17 known XLID genes in patients from 135 families and found eight single-nucleotide changes that were absent in controls. For four mutations affecting ATRX (p.1761M>T), PQBP1 (p.155R>X) and SLC6A8 (p.390P>L and p.477S>L), we provide evidence for a functional involvement of these changes in the aetiology of intellectual disability.

• 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.

• 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.

• A distinctive gene expression fingerprint in mentally retarded male patients reflects disease-causing defects in the histone demethylase KDM5C.

  Authors: Lars R Jensen, Heinz Bartenschlager, Sinitdhorn Rujirabanjerd, Andreas Tzschach, Astrid Nümann, Andreas R Janecke, Ralf Spörle, Sigmar Stricker, Martine Raynaud, John Nelson, Anna Hackett, Jean-Pierre Fryns, Jamel Chelly, Arjan Pm de Brouwer, Ben Hamel, Jozef Gecz, Hans-Hilger Ropers, Andreas W Kuss

  PathoGenetics. 02/2010; 3(1):2.

  Mental retardation is a genetically heterogeneous disorder, as more than 90 genes for this disorder has been found on the X chromosome alone. In addition the majority of patients are non-syndromic inMental retardation is a genetically heterogeneous disorder, as more than 90 genes for this disorder has been found on the X chromosome alone. In addition the majority of patients are non-syndromic in that they do not present with clinically recognisable features. This makes it difficult to determine the molecular cause of this disorder on the basis of the phenotype alone. Mutations in KDM5C (previously named SMCX or JARID1C), a gene that encodes a transcriptional regulator with histone demethylase activity specific for dimethylated and trimethylated H3K4, are a comparatively frequent cause of non-syndromic X-linked mental retardation (NS-XLMR). Specific transcriptional targets of KDM5C, however, are still unknown and the effects of KDM5C deficiency on gene expression have not yet been investigated. By whole-mount in situ hybridisation we showed that the mouse homologue of KDM5C is expressed in multiple tissues during mouse development.We present the results of gene expression profiling performed on lymphoblastoid cell lines as well as blood from patients with mutations in KDM5C. Using whole genome expression arrays and quantitative reverse transcriptase polymerase chain reaction (QRT-PCR) experiments, we identified several genes, including CMKOR1, KDM5B and KIAA0469 that were consistently deregulated in both tissues. Our findings shed light on the pathological mechanisms underlying mental retardation and have implications for future diagnostics of this heterogeneous disorder.

• 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.

• Identification of mutations in TRAPPC9, which encodes the NIK- and IKK-beta-binding protein, in nonsyndromic autosomal-recessive mental retardation.

  Authors: Asif Mir, Liana Kaufman, Abdul Noor, Mahdi M. Motazacker, Talal Jamil, Matloob Azam, Kimia Kahrizi, Muhammad Arshad Rafiq, Rosanna Weksberg, Tanveer Nasr, Farooq Naeem, Andreas Tzschach, Andreas W Kuss, Gisele E. Ishak, Dan Doherty, H Hilger Ropers, A. James Barkovich, Hossein Najmabadi, Muhammad Ayub, John B Vincent

  American journal of human genetics. 12/2009; 85(6):909-15.

  Mental retardation/intellectual disability is a devastating neurodevelopmental disorder with serious impact on affected individuals and their families, as well as on health and social services. ItMental retardation/intellectual disability is a devastating neurodevelopmental disorder with serious impact on affected individuals and their families, as well as on health and social services. It occurs with a prevalence of approximately 2%, is an etiologically heterogeneous condition, and is frequently the result of genetic aberrations. Autosomal-recessive forms of nonsyndromic MR (NS-ARMR) are believed to be common, yet only five genes have been identified. We have used homozygosity mapping to search for the gene responsible for NS-ARMR in a large Pakistani pedigree. Using Affymetrix 5.0 single nucleotide polymorphism (SNP) microarrays, we identified a 3.2 Mb region on 8q24 with a continuous run of 606 homozygous SNPs shared among all affected members of the family. Additional genotype data from microsatellite markers verified this, allowing us to calculate a two-point LOD score of 5.18. Within this region, we identified a truncating homozygous mutation, R475X, in exon 7 of the gene TRAPPC9. In a second large NS-ARMR/ID family, previously linked to 8q24 in a study of Iranian families, we identified a 4 bp deletion within exon 14 of TRAPPC9, also segregating with the phenotype and truncating the protein. This gene encodes NIK- and IKK-beta-binding protein (NIBP), which is involved in the NF-kappaB signaling pathway and directly interacts with IKK-beta and MAP3K14. Brain magnetic resonance imaging of affected individuals indicates the presence of mild cerebral white matter hypoplasia. Microcephaly is present in some but not all affected individuals. Thus, to our knowledge, this is the sixth gene for NS-ARMR to be discovered.

• Chromosome deletions in 13q33-34: report of four patients and review of the literature.

  Authors: Joanna Walczak-Sztulpa, Marzena Wisniewska, Anna Latos-Bielenska, Maja Linné, Christina Kelbova, Britta Belitz, Lutz Pfeiffer, Vera Kalscheuer, Fikret Erdogan, Andreas W Kuss, Hans-Hilger Ropers, Reinhard Ullmann, Andreas Tzschach

  American journal of medical genetics. Part A. 03/2008; 146(3):337-42.

  Deletions of chromosome bands 13q33-34 are rare. Patients with such deletions have mental retardation, microcephaly, and distinct facial features. Male patients frequently also have genitalDeletions of chromosome bands 13q33-34 are rare. Patients with such deletions have mental retardation, microcephaly, and distinct facial features. Male patients frequently also have genital malformations. We report on four patients with three overlapping deletions of 13q33-34 that have been characterized by tiling-path array-CGH. Patient 1 had mental retardation and microcephaly with an interstitial 4.7 Mb deletion and a translocation t(12;13)(q13.3;q32.3). His mother (Patient 2), who also had mental retardation and microcephaly, carried the identical chromosome aberration. Patient 3 was a girl with a de novo insertion ins(7;13)(p15.1;q22q31) and interstitial 4.5 Mb deletion in 13q33-34. She had mental retardation and microcephaly. Patient 4 was a newborn boy with severe genital malformation (penoscrotal transposition and hypospadias) and microcephaly. He had a de novo ring chromosome 13 lacking the terminal 9.3 Mb of 13q. Karyotype-phenotype comparisons of these and eight previously published del13q33-34 patients suggest EFNB2 as a candidate gene for genital malformations in males. Molecular cytogenetic definition of a common deleted region in all patients suggests ARHGEF7 as a candidate gene for mental retardation and microcephaly.

• Mutation screening of brain-expressed X-chromosomal miRNA genes in 464 patients with nonsyndromic X-linked mental retardation.

  Authors: Wei Chen, Lars R Jensen, Jozef Gecz, Jean-Pierre Fryns, Claude Moraine, Arjan de Brouwer, Jamel Chelly, Bettina Moser, H Hilger Ropers, Andreas W Kuss

  European journal of human genetics : EJHG. 04/2007; 15(3):375-8.

  MiRNAs are small noncoding RNAs that control the expression of target genes at the post-transcriptional level and have been reported to modulate various biological processes. Their function asMiRNAs are small noncoding RNAs that control the expression of target genes at the post-transcriptional level and have been reported to modulate various biological processes. Their function as regulatory factors in gene expression renders them attractive candidates for harbouring genetic variants with subtle effects on IQ. In an attempt to investigate the potential role of miRNAs in the aetiology of X-linked mental retardation, we have examined all 13 known, brain-expressed X-chromosomal miRNAs in a cohort of 464 patients with non-syndromic X-linked MR and found four nucleotide changes in three different pre-miRNA hairpins. All the observed changes appear to be functionally neutral which, taken together with the rarity of detected nucleotide changes in miRNA genes, may reflect strong selection and thus underline the functional importance of miRNAs.

• 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.

• Mutation frequencies of X-linked mental retardation genes in families from the EuroMRX consortium.

  Authors: Arjan P M de Brouwer, Helger G Yntema, Tjitske Kleefstra, Dorien Lugtenberg, Astrid R Oudakker, Bert B A de Vries, Hans van Bokhoven, Hilde Van Esch, Suzanne G M Frints, Guy Froyen [......] Gillian Turner, Tod Fullston, Jozef Gecz, Andreas W Kuss, Andreas Tzschach, Lars Riff Jensen, Steffen Lenzner, Vera M Kalscheuer, Hans-Hilger Ropers, Ben C J Hamel

  Human mutation. 03/2007; 28(2):207-8.

  The EuroMRX family cohort consists of about 400 families with non-syndromic and 200 families with syndromic X-linked mental retardation (XLMR). After exclusion of Fragile X (Fra X) syndrome, probandsThe EuroMRX family cohort consists of about 400 families with non-syndromic and 200 families with syndromic X-linked mental retardation (XLMR). After exclusion of Fragile X (Fra X) syndrome, probands from these families were tested for mutations in the coding sequence of 90 known and candidate XLMR genes. In total, 73 causative mutations were identified in 21 genes. For 42% of the families with obligate female carriers, the mental retardation phenotype could be explained by a mutation. There was no difference between families with (lod score >2) or without (lod score <2) significant linkage to the X chromosome. For families with two to five affected brothers (brother pair=BP families) only 17% of the MR could be explained. This is significantly lower (P=0.0067) than in families with obligate carrier females and indicates that the MR in about 40% (17/42) of the BP families is due to a single genetic defect on the X chromosome. The mutation frequency of XLMR genes in BP families is lower than can be expected on basis of the male to female ratio of patients with MR or observed recurrence risks. This might be explained by genetic risk factors on the X chromosome, resulting in a more complex etiology in a substantial portion of XLMR patients. The EuroMRX effort is the first attempt to unravel the molecular basis of cognitive dysfunction by large-scale approaches in a large patient cohort. Our results show that it is now possible to identify 42% of the genetic defects in non-syndromic and syndromic XLMR families with obligate female carriers.

• 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.

• OLA-DRB1 microsatellite variants are associated with ovine growth and reproduction traits.

  Authors: Hermann Geldermann, Manzoor R Mir, Andreas W Kuss, Heinz Bartenschlager

  Genetics, selection, evolution. : GSE. 38(4):431-44.

  The DRB1 intron 2 (GT)(n)(GA)(m) microsatellite was genotyped in experimental flocks of seven Merinoland rams and 249 ewes as well as their offspring (381 lambs) from consecutive lambings. A total ofThe DRB1 intron 2 (GT)(n)(GA)(m) microsatellite was genotyped in experimental flocks of seven Merinoland rams and 249 ewes as well as their offspring (381 lambs) from consecutive lambings. A total of 16 DRB1 alleles were detected, ranging between 353 and 857 bp. In comparison with carriers of other alleles, the ewes carrying the predominant 411 bp allele had higher values of all the recorded fertility traits. For ewes carrying the 394 and 857 bp alleles, the birth weight of lambs was about 400 g higher as compared to the residual group of ewes. The observed associations could be due to differences in disease resistance, cell recognition or tissue differentiation between carriers of various MHC haplotypes which can in turn affect individual fertility and growth performance.

• Identification of Mutations in TRAPPC9, which Encodes the NIK- and IKK-β-Binding Protein, in Nonsyndromic Autosomal-Recessive Mental Retardation

  Authors: Asif Mir, Liana Kaufman, Abdul Noor, Mahdi M. Motazacker, Talal Jamil, Matloob Azam, Kimia Kahrizi, Muhammad Arshad Rafiq, Rosanna Weksberg, Tanveer Nasr, Farooq Naeem, Andreas Tzschach, Andreas W Kuss, Gisele E. Ishak, Dan Doherty, Hans-Hilger Ropers, A. James Barkovich, Hossein Najmabadi, Muhammad Ayub, John B Vincent

  American Journal of Human Genetics, v.85, 909-915 (2009).

  Mental retardation/intellectual disability is a devastating neurodevelopmental disorder with serious impact on affected individuals and their families, as well as on health and social services. ItMental retardation/intellectual disability is a devastating neurodevelopmental disorder with serious impact on affected individuals and their families, as well as on health and social services. It occurs with a prevalence of ∼2%, is an etiologically heterogeneous condition, and is frequently the result of genetic aberrations. Autosomal-recessive forms of nonsyndromic MR (NS-ARMR) are believed to be common, yet only five genes have been identified. We have used homozygosity mapping to search for the gene responsible for NS-ARMR in a large Pakistani pedigree. Using Affymetrix 5.0 single nucleotide polymorphism (SNP) microarrays, we identified a 3.2 Mb region on 8q24 with a continuous run of 606 homozygous SNPs shared among all affected members of the family. Additional genotype data from microsatellite markers verified this, allowing us to calculate a two-point LOD score of 5.18. Within this region, we identified a truncating homozygous mutation, R475X, in exon 7 of the gene TRAPPC9. In a second large NS-ARMR/ID family, previously linked to 8q24 in a study of Iranian families, we identified a 4 bp deletion within exon 14 of TRAPPC9, also segregating with the phenotype and truncating the protein. This gene encodes NIK- and IKK-β-binding protein (NIBP), which is involved in the NF-κB signaling pathway and directly interacts with IKK-β and MAP3K14. Brain magnetic resonance imaging of affected individuals indicates the presence of mild cerebral white matter hypoplasia. Microcephaly is present in some but not all affected individuals. Thus, to our knowledge, this is the sixth gene for NS-ARMR to be discovered.