Journal Article

Interpreting the pathogenicity of Joubert syndrome missense variants in Caenorhabditis elegans

Lange, Karen I., Blacque, Oliver E., Kucharska, Katarzyna, Tsiropoulou, Sofia

2021

Overview

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.

• Publisher: The Company of Biologists Ltd,The Company of Biologists
• Subject: Abnormalities, Multiple - genetics / Abnormalities, Multiple - physiopathology / Alleles / Animals / b9d2 / c. elegans / Caenorhabditis elegans - genetics / Caenorhabditis elegans Proteins - metabolism / Cerebellum - abnormalities / Cerebellum - physiopathology / cilia / Cilia - metabolism / CRISPR / CRISPR-Cas Systems / Disease / Disease Models, Animal / Eye Abnormalities - genetics / Eye Abnormalities - physiopathology / Gene Editing / Genes / Genetic Association Studies / Genome editing / Genomes / Genotype / Homeostasis / Humans / joubert syndrome / Kidney Diseases, Cystic - genetics / Kidney Diseases, Cystic - physiopathology / Localization / Membrane Proteins - metabolism / mksr-2 / Mutation / Mutation, Missense / Nematodes / Phenotype / Proteins / Retina - abnormalities / Retina - physiopathology / transition zone / Worms