4.5 Article

Interpreting the pathogenicity of Joubert syndrome missense variants in Caenorhabditis elegans

Journal

DISEASE MODELS & MECHANISMS
Volume 14, Issue 1, Pages -

Publisher

COMPANY BIOLOGISTS LTD
DOI: 10.1242/dmm.046631

Keywords

B9D2; C; elegans; Joubert syndrome; Cilia; MKSR-2; Transition zone

Funding

  1. Science Foundation Ireland (SFI)
  2. Biotechnology and Biological Sciences Research Council (BBSRC) [16/BBSRC/3394]

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By using a leading model organism, Caenorhabditis elegans, and gene editing, researchers have characterized two missense variants in the mksr-2/B9D2 gene associated with Joubert syndrome. The study confirms the pathogenicity of these variants in worms, showing disruptions in cilia/TZ structure and function. The findings demonstrate C. elegans as a model for interpreting JBTS mutations and provide insight into the organization of the MKS module.
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.

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