Striessnig J.,Institute of Pharmacy |
Bolz H.J.,Bioscientia Center for Human Genetics |
Bolz H.J.,University of Cologne |
Koschak A.,Institute of Pharmacy
Pflugers Archiv European Journal of Physiology | Year: 2010
Voltage-gated Ca2+ channels couple membrane depolarization to Ca2+-dependent intracellular signaling events. This is achieved by mediating Ca2+ ion influx or by direct conformational coupling to intracellular Ca2+ release channels. The family of Cav1 channels, also termed L-type Ca2+ channels (LTCCs), is uniquely sensitive to organic Ca2+ channel blockers and expressed in many electrically excitable tissues. In this review, we summarize the role of LTCCs for human diseases caused by genetic Ca2+ channel defects (channelopathies). LTCC dysfunction can result from structural aberrations within their pore-forming α1 subunits causing hypokalemic periodic paralysis and malignant hyperthermia sensitivity (Cav1.1 α1), incomplete congenital stationary night blindness (CSNB2; Cav1.4 α1), and Timothy syndrome (Cav1.2 α1; reviewed separately in this issue). Cav1.3 α1 mutations have not been reported yet in humans, but channel loss of function would likely affect sinoatrial node function and hearing. Studies in mice revealed that LTCCs indirectly also contribute to neurological symptoms in Ca2+ channelopathies affecting non-LTCCs, such as Cav2.1 α1 in tottering mice. Ca 2+ channelopathies provide exciting disease-related molecular detail that led to important novel insight not only into disease pathophysiology but also to mechanisms of channel function. © The Author(s) 2010.
Vache C.,Montpellier University Hospital Center |
Besnard T.,Montpellier University Hospital Center |
Besnard T.,French Institute of Health and Medical Research |
Besnard T.,Montpellier University |
And 17 more authors.
Human Mutation | Year: 2012
USH2A sequencing in three affected members of a large family, referred for the recessive USH2 syndrome, identified a single pathogenic alteration in one of them and a different mutation in the two affected nieces. As the patients carried a common USH2A haplotype, they likely shared a mutation not found by standard sequencing techniques. Analysis of RNA from nasal cells in one affected individual identified an additional pseudoexon (PE) resulting from a deep intronic mutation. This was confirmed by minigene assay. This is the first example in Usher syndrome (USH) with a mutation causing activation of a PE. The finding of this alteration in eight other individuals of mixed European origin emphasizes the importance of including RNA analysis in a comprehensive diagnostic service. Finally, this mutation, which would not have been found by whole-exome sequencing, could offer, for the first time in USH, the possibility of therapeutic correction by antisense oligonucleotides (AONs). © 2011 Wiley Periodicals, Inc.
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.
Rabstein S.,Ruhr University Bochum |
Harth V.,University of Hamburg |
Justenhoven C.,Bioscientia Center for Human Genetics |
Pesch B.,Ruhr University Bochum |
And 9 more authors.
Chronobiology International | Year: 2014
Objectives: The role of genetic variants and environmental factors in breast cancer etiology has been intensively studied in the last decades. Gene-environment interactions are now increasingly being investigated to gain more insights into the development of breast cancer, specific subtypes, and therapeutics. Recently, night shift work that involves circadian disruption has gained rising interest as a potential non-genetic breast cancer risk factor. Here, we analyzed genetic polymorphisms in genes of cellular clocks, melatonin biosynthesis and signaling and their association with breast cancer as well as gene-gene and gene-night work interactions in a German case-control study on breast cancer. Methods: GENICA is a population-based case-control study on breast cancer conducted in the Greater Region of Bonn. Associations between seven polymorphisms in circadian genes (CLOCK, NPAS2, ARTNL, PER2 and CRY2), genes of melatonin biosynthesis and signaling (AANAT and MTNR1B) and breast cancer were analyzed with conditional logistic regression models, adjusted for potential confounders for 1022 cases and 1014 controls. Detailed shift-work information was documented for 857 breast cancer cases and 892 controls. Gene-gene and gene-shiftwork interactions were analyzed using model-based multifactor dimensionality reduction (mbMDR). Results: For combined heterozygotes and rare homozygotes a slightly elevated breast cancer risk was found for rs8150 in gene AANAT (OR 1.17; 95% CI 1.01-1.36), and a reduced risk for rs3816358 in gene ARNTL (OR 0.82; 95% CI 0.69-0.97) in the complete study population. In the subgroup of shift workers, rare homozygotes for rs10462028 in the CLOCK gene had an elevated risk of breast cancer (OR for AA vs. GG: 3.53; 95% CI 1.09-11.42). Shift work and CLOCK gene interactions were observed in the two-way interaction analysis. In addition, gene-shiftwork interactions were detected for MTNR1B with NPAS2 and ARNTL. Conclusions: In conclusion, the results of our population-based case-control study support a putative role of the CLOCK gene in the development of breast cancer in shift workers. In addition, higher order interaction analyses suggest a potential relevance of MTNR1B with the key transcriptional factor NPAS2 with ARNTL. Hence, in the context of circadian disruption, multivariable models should be preferred that consider a wide range of polymorphisms, e.g. that may influence chronotype or light sensitivity. The investigation of these interactions in larger studies is needed. © 2014 Informa Healthcare USA, Inc.
Elsayed S.M.,Medical Genetics Center |
Elsayed S.M.,Ain Shams University |
Heller R.,University of Cologne |
Thoenes M.,University of Cologne |
And 10 more authors.
European Journal of Human Genetics | Year: 2014
Although many genes have been identified for the autosomal recessive cerebellar ataxias (ARCAs), several patients are unlinked to the respective loci, suggesting further genetic heterogeneity. We combined homozygosity mapping and exome sequencing in a consanguineous Egyptian family with congenital ARCA, mental retardation and pyramidal signs. A homozygous 5-bp deletion in SPTBN2, the gene whose in-frame mutations cause autosomal dominant spinocerebellar ataxia type 5, was shown to segregate with ataxia in the family. Our findings are compatible with the concept of truncating SPTBN2 mutations acting recessively, which is supported by disease expression in homozygous, but not heterozygous, knockout mice, ataxia in Beagle dogs with a homozygous frameshift mutation and, very recently, a homozygous SPTBN2 nonsense mutation underlying infantile ataxia and psychomotor delay in a human family. As there was no evidence for mutations in 23 additional consanguineous families, SPTBN2-related ARCA is probably rare. © 2014 Macmillan Publishers Limited All rights reserved.