RRC ID 46163
著者 Masyukova SV, Winkelbauer ME, Williams CL, Pieczynski JN, Yoder BK.
タイトル Assessing the pathogenic potential of human Nephronophthisis disease-associated NPHP-4 missense mutations in C. elegans.
ジャーナル Hum Mol Genet
Abstract A spectrum of complex oligogenic disorders called the ciliopathies have been connected to dysfunction of cilia. Among the ciliopathies are Nephronophthisis (NPHP), characterized by cystic kidney disease and retinal degeneration, and Meckel-Gruber syndrome (MKS), a gestational lethal condition with skeletal abnormalities, cystic kidneys and CNS malformation. Mutations in multiple genes have been identified in NPHP and MKS patients, and an unexpected finding has been that mutations within the same gene can cause either disorder. Further, there is minimal genotype-phenotype correlation and despite recessive inheritance, numerous patients were identified as having a single heterozygous mutation. This has made it difficult to determine the significance of these mutations on disease pathogenesis and led to the hypothesis that clinical presentation in an individual will be determined by genetic interactions between mutations in multiple cilia-related genes. Here we utilize Caenorhabditis elegans and cilia-associated behavioral and morphologic assays to evaluate the pathogenic potential of eight previously reported human NPHP4 missense mutations. We assess the impact of these mutations on C. elegans NPHP-4 function, localization and evaluate potential interactions with mutations in MKS complex genes, mksr-2 and mksr-1. Six out of eight nphp-4 mutations analyzed alter ciliary function, and three of these modify the severity of the phenotypes caused by disruption of mksr-2 and mksr-1. Collectively, our studies demonstrate the utility of C. elegans as a tool to assess the pathogenicity of mutations in ciliopathy genes and provide insights into the complex genetic interactions contributing to the diversity of phenotypes associated with cilia disorders.
巻・号 20(15)
ページ 2942-54
公開日 2011-8-1
DOI 10.1093/hmg/ddr198
PII ddr198
PMID 21546380
PMC PMC3131040
MeSH Animals Animals, Genetically Modified Caenorhabditis elegans Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Genetic Association Studies Humans Mutation, Missense / genetics Mutation, Missense / physiology* Proteins / genetics* Proteins / metabolism*
IF 5.101
引用数 6
WOS 分野 GENETICS & HEREDITY BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
線虫 tm925 tm2452