RRC ID 65370
Author Lange KI, Tsiropoulou S, Kucharska K, Blacque OE.
Title Interpreting the pathogenicity of Joubert syndrome missense variants in Caenorhabditis elegans.
Journal 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.
Volume 14(1)
Published 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
Resource
C.elegans tm2452 tm925