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Köln, Germany

Ebermann I.,University of Cologne | Phillips J.B.,University of Oregon | Liebau M.C.,McGill University | Koenekoop R.K.,McGill University | And 19 more authors.
Journal of Clinical Investigation | Year: 2010

Usher syndrome is a genetically heterogeneous recessive disease characterized by hearing loss and retinitis pigmentosa (RP). It frequently presents with unexplained, often intrafamilial, variability of the visual phenotype. Although 9 genes have been linked with Usher syndrome, many patients do not have mutations in any of these genes, suggesting that there are still unidentified genes involved in the syndrome. Here, we have determined that mutations in PDZ domain-containing 7 (PDZD7), which encodes a homolog of proteins mutated in Usher syndrome subtype 1C (USH1C) and USH2D, contribute to Usher syndrome. Mutations in PDZD7 were identified only in patients with mutations in other known Usher genes. In a set of sisters, each with a homozygous mutation in USH2A, a frame-shift mutation in PDZD7 was present in the sister with more severe RP and earlier disease onset. Further, heterozygous PDZD7 mutations were present in patients with truncating mutations in USH2A, G protein-coupled receptor 98 (GPR98; also known as USH2C), and an unidentified locus. We validated the human genotypes using zebrafish, and our findings were consistent with digenic inheritance of PDZD7 and GPR98, and with PDZD7 as a retinal disease modifier in patients with USH2A. Pdzd7 knockdown produced an Usher-like phenotype in zebrafish, exacerbated retinal cell death in combination with ush2a or gpr98, and reduced Gpr98 localization in the region of the photoreceptor connecting cilium. Our data challenge the view of Usher syndrome as a traditional Mendelian disorder and support the reclassification of Usher syndrome as an oligogenic disease. Source

Gundacker C.,Medical University of Vienna | Gencik M.,Praxis fur Humangenetik | Hengstschlager M.,Medical University of Vienna
Mutation Research - Reviews in Mutation Research | Year: 2010

The heavy metals mercury and lead are well-known and significant developmental neurotoxicants. This review summarizes the genetic factors that modify their toxicokinetics. Understanding toxicokinetics (uptake, biotransformation, distribution, and elimination processes) is a key precondition to understanding the individual health risks associated with exposure. We selected candidate susceptibility genes when evidence was available for (1) genes/proteins playing a significant role in mercury and lead toxicokinetics, (2) gene expression/protein activity being induced by these metals, and (3) mercury and lead toxicokinetics being affected by gene knockout/knockdown or (4) by functional gene polymorphisms. The genetic background is far better known for mercury than for lead toxicokinetics. Involved are genes encoding L-type amino acid transporters, organic anion transporters, glutathione (GSH)-related enzymes, metallothioneins, and transporters of the ABC family. Certain gene variants can influence mercury toxicokinetics, potentially explaining part of the variable susceptibility to mercury toxicity. Delta-aminolevulinic acid dehydratase (ALAD), vitamin D receptor (VDR) and hemochromatosis (HFE) gene variants are the only well-established susceptibility markers of lead toxicity in humans. Many gaps remain in our knowledge about the functional genomics of this issue. This calls for studies to detect functional gene polymorphisms related to mercury- and lead-associated disease phenotypes, to demonstrate the impact of functional polymorphisms and gene knockout/knockdown in relation to toxicity, to confirm the in vivo relevance of genetic variation, and to examine gene-gene interactions on the respective toxicokinetics. Another crucial aspect is knowledge on the maternal-fetal genetic background, which modulates fetal exposure to these neurotoxicants. To completely define the genetically susceptible risk groups, research is also needed on the genes/proteins involved in the toxicodynamics, i.e., in the mechanisms causing adverse effects in the brain. Studies relating the toxicogenetics to neurodevelopmental disorders are lacking (mercury) or very scarce (lead). Thus, the extent of variability in susceptibility to heavy metal-associated neurological outcomes is poorly characterized. © 2010 Elsevier B.V. Source

Gremer L.,Heinrich Heine University Dusseldorf | de Luca A.,Casa Sollievo della Sofferenza CSS Hospital | Merbitz-Zahradnik T.,Heinrich Heine University Dusseldorf | Dallapiccola B.,Casa Sollievo della Sofferenza CSS Hospital | And 4 more authors.
Human Molecular Genetics | Year: 2010

Costello syndrome (CS) is a developmental disorder characterized by postnatal reduced growth, facial dysmorphism, cardiac defects, mental retardation and skin and musculo-skeletal defects. CS is caused by HRAS germline mutations. In the majority of cases, mutations affect Gly12 and Gly13 and are associated with a relatively homogeneous phenotype. The same amino acid substitutions are well known as somatic mutations in human tumors and promote constitutive HRAS activation by impairing its GTPase activity. In a small number of cases with mild phenotype, a second class of substitutions involving codons 117 and 146 and affecting GTP/GDP binding has been described. Here, we report on the identification and functional characterization of two different three-nucleotide duplications resulting in a duplication of glutamate 37 (p.E37dup) associated with a homogeneous phenotype reminiscent of CS. Ectopic expression of HRASE37dup in COS-7 cells resulted in enhanced growth factor-dependent stimulation of the MEK-ERK and phosphoinositide 3-kinase (PI3K)-AKT signaling pathways. Recombinant HRASE37dup was characterized by slightly increased GTP/GDP dissociation, lower intrinsic GTPase activity and complete resistance to neurofibromin 1 GTPase-activating protein (GAP) stimulation due to dramatically reduced binding. Co-precipitation of GTP-bound HRASE37dup by various effector proteins, however, was inefficient because of drastically diminished binding affinities. Thus, although HRASE37dup is predominantly present in the active, GTP-bound state, it promotes only a weak hyperactivation of downstream signaling pathways. These findings provide evidence that the mildly enhanced signal flux through the MAPK and PI3K-AKT cascades promoted by these disease-causing germline HRAS alleles results from a balancing effect between a profound GAP insensitivity and inefficient binding to effector proteins. © The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org. Source

Deardorff M.A.,Childrens Hospital of Philadelphia | Deardorff M.A.,University of Pennsylvania | Wilde J.J.,Childrens Hospital of Philadelphia | Albrecht M.,University of Lubeck | And 31 more authors.
American Journal of Human Genetics | Year: 2012

The evolutionarily conserved cohesin complex was originally described for its role in regulating sister-chromatid cohesion during mitosis and meiosis. Cohesin and its regulatory proteins have been implicated in several human developmental disorders, including Cornelia de Lange (CdLS) and Roberts syndromes. Here we show that human mutations in the integral cohesin structural protein RAD21 result in a congenital phenotype consistent with a "cohesinopathy." Children with RAD21 mutations display growth retardation, minor skeletal anomalies, and facial features that overlap findings in individuals with CdLS. Notably, unlike children with mutations in NIPBL, SMC1A, or SMC3, these individuals have much milder cognitive impairment than those with classical CdLS. Mechanistically, these mutations act at the RAD21 interface with the other cohesin proteins STAG2 and SMC1A, impair cellular DNA damage response, and disrupt transcription in a zebrafish model. Our data suggest that, compared to loss-of-function mutations, dominant missense mutations result in more severe functional defects and cause worse structural and cognitive clinical findings. These results underscore the essential role of RAD21 in eukaryotes and emphasize the need for further understanding of the role of cohesin in human development. © 2012 by The American Society of Human Genetics. All rights reserved. Source

Rind N.,Center for Child and Adolescent Medicine | Schmeiser V.,University of Regensburg | Thiel C.,Center for Child and Adolescent Medicine | Absmanner B.,University of Regensburg | And 6 more authors.
Human Molecular Genetics | Year: 2010

A new type of congenital disorders of glycosylation, designated CDG-Ip, is caused by the deficiency of GDP-Man:Man3GlcNAc2-PP-dolichol-α1,2-mannosyltransferase, encoded by the human ortholog of ALG11 from yeast. The patient presented with a multisystemic disorder characterized by muscular hypotonia, seizures, developmental retardation and death at the age of 2 years. The isoelectric focusing pattern of the patient's serum transferrin showed the partial loss of complete N-glycan side chains, which is a characteristic sign for CDG-I. Analysis of dolichol-linked oligosaccharides in patient-derived fibroblasts revealed an accumulation of Man3GlcNAc2-PP-dolichol and Man4GlcNAc2-PP-dolichol. Determination of mannosyltransferase activities of early steps of lipid-linked oligosaccharide biosynthesis in fibroblasts indicated that the patient was deficient in elongating Man3GlcNAc2-PP-dolichol. These findings gave rise to genetic analysis of the hALG11 cDNA, in which homozygosity for mutation c.T257C (p.L86S) was identified. Verification of the mutation as a primary cause for the genetic defect was proved by retroviral expression of human wild-type and mutated ALG11 cDNA in patient-derived fibroblasts as well as using a yeast alg11 deletion strain as a heterologous expression system for hALG11 variants. Immunofluorescence examinations combined with western blotting showed no differences of intracellular localization or expression of ALG11 between control and patient fibroblasts, respectively, indicating no mislocalization or degradation of the mutated transferase. © The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org. Source

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