Identification of a novel MKS locus defined by TMEM107 mutation
| Autor: | Rana Alomar, Mohammed Zain Seidahmed, Fowzan S. Alkuraya, Seema Kapoor, Elham Al Mardawi, Mohamed Ibrahim Khalil, Niema Ibrahim, Amal Alhashem, Agaadir Almoisheer, Ankur Singh, Mohamed Abouelhoda, Maha Alnemer, Zainab A. Babay, Eissa Faqeih, Samira Sogaty, Ranad Shaheen, Nada Alsahan, Dorota Monies, Wesam Kurdi, Manisha Goyal, Nada Al Tassan |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Genotype DNA Mutational Analysis Locus (genetics) Biology Ciliopathies Consanguinity Genetic Heterogeneity Ciliogenesis Genetics medicine Humans Hedgehog Proteins Cilia Molecular Biology Genetics (clinical) Exome sequencing Alleles Encephalocele Cystic kidney Polycystic Kidney Diseases urogenital system Genetic heterogeneity Cilium Membrane Proteins General Medicine medicine.disease Pedigree Ciliopathy Genetic Loci Mutation Female Retinitis Pigmentosa Ciliary Motility Disorders Signal Transduction |
| Zdroj: | Human molecular genetics. 24(18) |
| ISSN: | 1460-2083 |
| Popis: | Meckel–Gruber syndrome (MKS) is a perinatally lethal disorder characterized by the triad of occipital encephalocele, polydactyly and polycystic kidneys. Typical of other disorders related to defective primary cilium (ciliopathies), MKS is genetically heterogeneous with mutations in a dozen genes to date known to cause the disease. In an ongoing effort to characterize MKS clinically and genetically, we implemented a gene panel and next-generation sequencing approach to identify the causal mutation in 25 MKS families. Of the three families that did not harbor an identifiable causal mutation by this approach, two mapped to a novel disease locus in which whole-exome sequencing revealed the likely causal mutation as a homozygous splicing variant in TMEM107, which we confirm leads to aberrant splicing and nonsense-mediated decay. TMEM107 had been independently identified in two mouse models as a cilia-related protein and mutant mice display typical ciliopathy phenotypes. Our analysis of patient fibroblasts shows marked ciliogenesis defect with an accompanying perturbation of sonic hedgehog signaling, highly concordant with the cellular phenotype in Tmem107 mutants. This study shows that known MKS loci account for the overwhelming majority of MKS cases but additional loci exist including MKS13 caused by TMEM107 mutation. |
| Databáze: | OpenAIRE |
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