論文 - 詳細
| RRC ID | 65370 |
|---|---|
| 著者 | Lange KI, Tsiropoulou S, Kucharska K, Blacque OE. |
| タイトル | Interpreting the pathogenicity of Joubert syndrome missense variants in Caenorhabditis elegans. |
| ジャーナル | Dis Model Mech |
| Abstract |
Ciliopathies are inherited disorders caused by defects in motile and non-motile (primary) cilia. Ciliopathy syndromes and associated gene variants are often highly pleiotropic and represent exemplars for interrogating genotype-phenotype correlations. Towards understanding disease mechanisms in the context of ciliopathy mutations, we have used a leading model organism for cilia and ciliopathy research, Caenorhabditis elegans, together with gene editing, to characterise two missense variants (P74S and G155S) in mksr-2/B9D2 associated with Joubert syndrome (JBTS). B9D2 functions within the Meckel syndrome (MKS) module at the ciliary base transition zone (TZ) compartment and regulates the molecular composition and sensory/signalling functions of the cilium. Quantitative assays of cilium/TZ structure and function, together with knock-in reporters, confirm that both variant alleles are pathogenic in worms. G155S causes a more severe overall phenotype and disrupts endogenous MKSR-2 organisation at the TZ. Recapitulation of the patient biallelic genotype shows that compound heterozygous worms phenocopy worms homozygous for P74S. The P74S and G155S alleles also reveal evidence of a very close functional association between the B9D2-associated B9 complex and MKS-2/TMEM216. Together, these data establish C. elegans as a model for interpreting JBTS mutations and provide further insight into MKS module organisation. This article has an associated First Person interview with the first author of the paper. |
| 巻・号 | 14(1) |
| 公開日 | 2021-1-1 |
| DOI | 10.1242/dmm.046631 |
| PII | dmm.046631 |
| PMID | 33234550 |
| PMC | PMC7859701 |
| MeSH | Abnormalities, Multiple / genetics* Abnormalities, Multiple / physiopathology Alleles Animals CRISPR-Cas Systems Caenorhabditis elegans / genetics* Caenorhabditis elegans Proteins / metabolism Cerebellum / abnormalities* Cerebellum / physiopathology Cilia / metabolism* Disease Models, Animal Eye Abnormalities / genetics* Eye Abnormalities / physiopathology Gene Editing Genetic Association Studies Genotype Humans Kidney Diseases, Cystic / genetics* Kidney Diseases, Cystic / physiopathology Membrane Proteins / metabolism Mutation Mutation, Missense* Phenotype Retina / abnormalities* Retina / physiopathology |
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 27 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 線虫 | tm2452 tm925 |