Hans-Hilger Ropers

Publications of Hans-Hilger Ropers

• Novel GDI1 mutation in a large family with nonsyndromic X-linked intellectual disability.

  Authors: Gertrud Strobl-Wildemann, Vera M Kalscheuer, Hao Hu, Klaus Wrogemann, Hans-Hilger Ropers, Andreas Tzschach

  American journal of medical genetics. Part A. 12/2011; 155A(12):3067-70.

  X-linked intellectual disability (XLID) is a heterogeneous disorder, and mutations in more than 90 genes have been associated with XLID to date. We report on a large multi-generational German familyX-linked intellectual disability (XLID) is a heterogeneous disorder, and mutations in more than 90 genes have been associated with XLID to date. We report on a large multi-generational German family in which the affected male family members had nonsyndromic intellectual disability, that is, they had neither abnormal body measurements nor any other significant clinical problems. Molecular genetic analysis revealed a frameshift mutation in GDI1 (c.1185_1186delAG; Ser396ProfsX15) that co-segregated with the disease. GDI1 encodes for the GDP-dissociation inhibitor alpha (αGDI), a protein involved in the regulation of the activity of Rab GTPases. Only three families with GDI1 mutations have been reported so far. The present family supports the lack of additional phenotypic features in patients with GDI1 mutations, rendering a clinical diagnosis of GDI1-associated XLID impossible. Thus, this family not only broadens the spectrum of GDI1 mutations but also emphasizes the need for parallel testing of all known genes associated with ID in patients with an unspecific phenotype.

• 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.

• Interstitial deletion of 14q24.3-q32.2 in a male patient with plagiocephaly, BPES features, developmental delay, and congenital heart defects.

  Authors: Sultan Cingöz, Iben Bache, Lise Bjerglund, Hans-Hilger Ropers, Niels Tommerup, Hanne Jensen, Karen Brøndum-Nielsen, Zeynep Tümer

  American journal of medical genetics. Part A. 01/2011; 155A(1):203-6.

  Distal interstitial deletions of chromosome 14 involving the 14q24-q23.2 region are rare, and only been reported so far in 20 patients. Ten of these patients were analyzed both clinically andDistal interstitial deletions of chromosome 14 involving the 14q24-q23.2 region are rare, and only been reported so far in 20 patients. Ten of these patients were analyzed both clinically and genetically. Here we present a de novo interstitial deletion of chromosome 14q24.3-q32.2 in a male patient with developmental delay, language impairment, plagiocephaly, BPES features (blepharophimosis, ptosis, epicanthus), and congenital heart defect. The deletion breakpoints were fine mapped using fluorescence in situ hybridization (FISH) and the size of the deletion is estimated to be approximately 23 Mb. Based on genotype-phenotype comparisons of the 10 previously published patients and the present case, we suggest that the shortest regions for deletion overlap may include candidate genes for speech impairment, mental retardation, and hypotonia.

• 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.

• 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.

• 11q14.1-11q22.1 deletion in a 1-year-old male with minor dysmorphic features.

  Authors: Ariana Kariminejad, Roxana Kariminejad, Andreas Tzschach, Hamid Najafi, Alischo Ahmed, Reinhard Ullmann, Hans-Hilger Ropers, Mohamad Hasan Kariminejad

  American journal of medical genetics. Part A. 10/2010; 152A(10):2651-5.

• Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.

  Authors: Sabine Endele, Georg Rosenberger, Kirsten Geider, Bernt Popp, Ceyhun Tamer, Irina Stefanova, Mathieu Milh, Fanny Kortüm, Angela Fritsch, Friederike K Pientka [......] Holger Tönnies, Nathalie Villeneuve, Laurent Villard, Bernhard Zabel, Martin Zenker, Bodo Laube, André Reis, Dagmar Wieczorek, Lionel Van Maldergem, Kerstin Kutsche

  Nature genetics. 10/2010; 42(11):1021-6.

  N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain. Two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits each form highlyN-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain. Two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits each form highly Ca²(+)-permeable cation channels which are blocked by extracellular Mg²(+) in a voltage-dependent manner. Either GRIN2B or GRIN2A, encoding the NMDA receptor subunits NR2B and NR2A, was found to be disrupted by chromosome translocation breakpoints in individuals with mental retardation and/or epilepsy. Sequencing of GRIN2B in 468 individuals with mental retardation revealed four de novo mutations: a frameshift, a missense and two splice-site mutations. In another cohort of 127 individuals with idiopathic epilepsy and/or mental retardation, we discovered a GRIN2A nonsense mutation in a three-generation family. In a girl with early-onset epileptic encephalopathy, we identified the de novo GRIN2A mutation c.1845C>A predicting the amino acid substitution p.N615K. Analysis of NR1-NR2A(N615K) (NR2A subunit with the p.N615K alteration) receptor currents revealed a loss of the Mg²(+) block and a decrease in Ca²(+) permeability. Our findings suggest that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected.

• Genetics of early onset cognitive impairment.

  Authors: Hans Hilger Ropers

  Annual review of genomics and human genetics. 09/2010; 11:161-87.

  Intellectual disability (ID) is the leading socio-economic problem of health care, but compared to autism and schizophrenia, it has received very little public attention. Important risk factors forIntellectual disability (ID) is the leading socio-economic problem of health care, but compared to autism and schizophrenia, it has received very little public attention. Important risk factors for ID are malnutrition, cultural deprivation, poor health care, and parental consanguinity. In the Western world, fetal alcohol exposure is the most common preventable cause. Most severe forms of ID have genetic causes. Cytogenetically detectable and submicroscopic chromosomal rearrangements account for approximately 25% of all cases. X-linked gene defects are responsible in 10-12% of males with ID; to date, 91 of these defects have been identified. In contrast, autosomal gene defects have been largely disregarded, but due to coordinated efforts and the advent of next-generation DNA sequencing, this is about to change. As shown for Fra(X) syndrome, this renewed focus on autosomal gene defects will pave the way for molecular diagnosis and prevention, shed more light on the pathogenesis of ID, and reveal new opportunities for therapy.

• WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.

  Authors: Hyung-Goo Kim, Jang-Won Ahn, Ingo Kurth, Reinhard Ullmann, Hyun-Taek Kim, Anita Kulharya, Kyung-Soo Ha, Yasuhide Itokawa, Irene Meliciani, Wolfgang Wenzel [......] Richard J Sherins, Takahiro Nagase, Mustafa Tekin, Soo-Hyun Kim, Cheol-Hee Kim, Hans-Hilger Ropers, James F Gusella, Vera Kalscheuer, Cheol Yong Choi, Lawrence C Layman

  American journal of human genetics. 09/2010; 87(4):465-79.

  By defining the chromosomal breakpoint of a balanced t(10;12) translocation from a subject with Kallmann syndrome and scanning genes in its vicinity in unrelated hypogonadal subjects, we haveBy defining the chromosomal breakpoint of a balanced t(10;12) translocation from a subject with Kallmann syndrome and scanning genes in its vicinity in unrelated hypogonadal subjects, we have identified WDR11 as a gene involved in human puberty. We found six patients with a total of five different heterozygous WDR11 missense mutations, including three alterations (A435T, R448Q, and H690Q) in WD domains important for β propeller formation and protein-protein interaction. In addition, we discovered that WDR11 interacts with EMX1, a homeodomain transcription factor involved in the development of olfactory neurons, and that missense alterations reduce or abolish this interaction. Our findings suggest that impaired pubertal development in these patients results from a deficiency of productive WDR11 protein interaction.

• TRPV1 acts as a synaptic protein and regulates vesicle recycling.

  Authors: Chandan Goswami, Nils Rademacher, Karl-Heinz Smalla, Vera Kalscheuer, Hans-Hilger Ropers, Eckart D Gundelfinger, Tim Hucho

  Journal of cell science. 06/2010; 123(Pt 12):2045-57.

  Electrophysiological studies demonstrate that transient receptor potential vanilloid subtype 1 (TRPV1) is involved in neuronal transmission. Although it is expressed in the peripheral as well as theElectrophysiological studies demonstrate that transient receptor potential vanilloid subtype 1 (TRPV1) is involved in neuronal transmission. Although it is expressed in the peripheral as well as the central nervous system, the questions remain whether TRPV1 is present in synaptic structures and whether it is involved in synaptic processes. In the present study we gathered evidence that TRPV1 can be detected in spines of cortical neurons, that it colocalizes with both pre- and postsynaptic proteins, and that it regulates spine morphology. Moreover, TRPV1 is also present in biochemically prepared synaptosomes endogenously. In F11 cells, a cell line derived from dorsal-root-ganglion neurons, TRPV1 is enriched in the tips of elongated filopodia and also at sites of cell-cell contact. In addition, we also detected TRPV1 in synaptic transport vesicles, and in transport packets within filopodia and neurites. Using FM4-64 dye, we demonstrate that recycling and/or fusion of these vesicles can be rapidly modulated by TRPV1 activation, leading to rapid reorganization of filopodial structure. These data suggest that TRPV1 is involved in processes such as neuronal network formation, synapse modulation and release of synaptic transmitters.

• 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.

• Characterization of an interstitial 4q32 deletion in a patient with mental retardation and a complex chromosome rearrangement.

  Authors: Andreas Tzschach, Corinna Menzel, Fikret Erdogan, Erman Salih Istifli, Martin Rieger, Angela Ovens-Raeder, Alfons Macke, Hans-Hilger Ropers, Reinhard Ullmann, Vera Kalscheuer

  American journal of medical genetics. Part A. 04/2010; 152A(4):1008-12.

  Interstitial deletions of chromosome band 4q32 are rare. We report on a 22-year-old female patient with a de novo interstitial deletion of chromosome 4q32 and a balanced translocationInterstitial deletions of chromosome band 4q32 are rare. We report on a 22-year-old female patient with a de novo interstitial deletion of chromosome 4q32 and a balanced translocation t(2;5)(p21;q12.1). Clinical problems of the patient comprised mild to moderate mental retardation, psychosis, obesity, broad nasal root, sparse lateral eyebrows, thin upper lip, short philtrum, micrognathia, and strabismus. Analysis by whole genome array CGH using an Agilent 244K oligonucleotide array and subsequent FISH using BAC clones from the 4q32 region revealed an unexpectedly complex rearrangement comprising a deletion of approximately 10 Mb in 4q32.1q32.3 and the insertion of two small fragments of 0.8 and 0.11 Mb originating from the derivative chromosome 4q32 into derivative chromosome 5q. The breakpoints of the t(2;5) translocation were mapped by BAC-FISH; no genes were disrupted by these breakpoints. The deleted interval in 4q32 harbored more than 30 genes, and haploinsufficiency of one or several of these genes is likely to have caused the clinical problems of the patient. Candidate genes for cognitive defects are GRIA2, GLRB, NPY1R, and NPY5R. In conclusion, this patient increases our knowledge about the phenotypic consequences of interstitial 4q32 deletions. Reports of patients with overlapping deletions will be needed to elucidate the role of individual genes and to establish genotype-phenotype correlations.

• Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly.

  Authors: Maila Giannandrea, Veronica Bianchi, Maria Lidia Mignogna, Alessandra Sirri, Salvatore Carrabino, Errico D'Elia, Matteo Vecellio, Silvia Russo, Francesca Cogliati, Lidia Larizza [......] Barbara Oehl-Jaschkowitz, Cindy Skinner, Charles E Schwartz, Jozef Gecz, Hilde Van Esch, Martine Raynaud, Jamel Chelly, Arjan P M de Brouwer, Daniela Toniolo, Patrizia D'Adamo

  American journal of human genetics. 02/2010; 86(2):185-95.

  Human Mental Retardation (MR) is a common and highly heterogeneous pediatric disorder affecting around 3% of the general population; at least 215 X-linked MR (XLMR) conditions have been described,Human Mental Retardation (MR) is a common and highly heterogeneous pediatric disorder affecting around 3% of the general population; at least 215 X-linked MR (XLMR) conditions have been described, and mutations have been identified in 83 different genes, encoding proteins with a variety of function, such as chromatin remodeling, synaptic function, and intracellular trafficking. The small GTPases of the RAB family, which play an essential role in intracellular vesicular trafficking, have been shown to be involved in MR. We report here the identification of mutations in the small GTPase RAB39B gene in two male patients. One mutation in family X (D-23) introduced a stop codon seven amino acids after the start codon (c.21C > A; p.Y7X). A second mutation, in the MRX72 family, altered the 5' splice site (c.215+1G > A) and normal splicing. Neither instance produced a protein. Mutations segregate with the disease in the families, and in some family members intellectual disabilities were associated with autism spectrum disorder, epileptic seizures, and macrocephaly. We show that RAB39B, a novel RAB GTPase of unknown function, is a neuronal-specific protein that is localized to the Golgi compartment. Its downregulation leads to an alteration in the number and morphology of neurite growth cones and a significant reduction in presynaptic buttons, suggesting that RAB39B is required for synapse formation and maintenance. Our results demonstrate developmental and functional neuronal alteration as a consequence of downregulation of RAB39B and emphasize the critical role of vesicular trafficking in the development of neurons and human intellectual abilities.

• 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.

• Recurrent deletion of ZNF630 at Xp11.23 is not associated with mental retardation.

  Authors: Dorien Lugtenberg, Luiz Zangrande-Vieira, Maria Kirchhoff, Annabel C Whibley, Astrid R Oudakker, Susanne Kjaergaard, Angela M Vianna-Morgante, Tjitske Kleefstra, Mariken Ruiter, Fernanda S Jehee [......] Jamel Chelly, Hans Hilger Ropers, Claude Moraine, Jozef Gècz, Jeroen Knijnenburg, Sarina G Kant, Ben C J Hamel, Carla Rosenberg, Hans van Bokhoven, Arjan P M de Brouwer

  American journal of medical genetics. Part A. 02/2010; 152A(3):638-45.

  ZNF630 is a member of the primate-specific Xp11 zinc finger gene cluster that consists of six closely related genes, of which ZNF41, ZNF81, and ZNF674 have been shown to be involved in mentalZNF630 is a member of the primate-specific Xp11 zinc finger gene cluster that consists of six closely related genes, of which ZNF41, ZNF81, and ZNF674 have been shown to be involved in mental retardation. This suggests that mutations of ZNF630 might influence cognitive function. Here, we detected 12 ZNF630 deletions in a total of 1,562 male patients with mental retardation from Brazil, USA, Australia, and Europe. The breakpoints were analyzed in 10 families, and in all cases they were located within two segmental duplications that share more than 99% sequence identity, indicating that the deletions resulted from non-allelic homologous recombination. In 2,121 healthy male controls, 10 ZNF630 deletions were identified. In total, there was a 1.6-fold higher frequency of this deletion in males with mental retardation as compared to controls, but this increase was not statistically significant (P-value = 0.174). Conversely, a 1.9-fold lower frequency of ZNF630 duplications was observed in patients, which was not significant either (P-value = 0.163). These data do not show that ZNF630 deletions or duplications are associated with mental retardation.

• Common Pathological Mutations in PQBP1 induce Nonsense-Mediated mRNA Decay and Enhance Exclusion of the Mutant Exome

  Authors: Luciana Musante, Stella-Amrei Kunde, Tina O. Sulistio, Ute Fischer, Astrid Grimme, Suzanna G.M. Frints, Charles E. Schwartz, Francisco Martinez, Corrado Romano, Hans Hilger Ropers, Vera M. Kalscheuer

  Human Mutation. 01/2010; 31(1):90-98.

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• 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.