Expanding the phenotype associated with biallelic WDR60 mutations: Siblings with retinal degeneration and polydactyly lacking other features of short rib thoracic dystrophies

Abstract

Ciliopathies are disorders of the primary cilium that can affect almost all organs and that are characterized by pleiotropy and extensive intra- and interfamilial phenotypic variability. Accordingly, mutations in the same gene can cause different ciliopathy phenotypes of varying severity. WDR60 encodes a protein thought to play a role in the primary cilium's intraflagellar transport machinery. Mutations in this gene are a rare cause of Jeune asphyxiating thoracic dystrophy (JATD) and short-rib polydactyly syndrome (SRPS). Here we report on a milder and distinct phenotype in a consanguineous Pakistani pedigree with two adolescent sisters affected by retinal degeneration and postaxial polydactyly, but lack of any further skeletal or chondrodysplasia features. By targeted high-throughput sequencing of genes known or suspected to be involved in ciliogenesis, we detected a novel homozygous N-terminal truncating WDR60 mutation (c.44delC/p.Ala15Glufs*90) that co-segregated with the disease in the family. Our finding broadens the spectrum of WDR60-related phenotypes and shows the utility of broad multigene panels during the genetic work-up of patients with ciliopathies.

WDR60-mediated dynein-2 loading into cilia powers retrograde IFT and transition zone crossing

“…We also show that WDR-60–deficient cilia are at least partially functional in chemotaxis and osmotic tolerance assays, contrasting with the strong behavioral defects exhibited by the xbx-1(null) mutant, which assembles severely shortened cilia. The mild chemotaxis and osmotic defects that we observe in wdr-60 mutants likely mirror the signaling defects underlying WDR60 -associated SRPS ( Cossu et al, 2016 ; Kakar et al, 2018 ; McInerney-Leo et al, 2013 ).…”

Interaction of WDR60 intermediate chain with TCTEX1D2 light chain of the dynein-2 complex is crucial for ciliary protein trafficking

“…, 2015 ; Cossu et al. , 2016 ; Kakar et al. , 2017 ), we then investigated the roles of these dynein-2 subunits in ciliary protein trafficking by establishing KO hTERT-RPE1 cell lines using the CRISPR/Cas9 system; although we analyzed two independent WDR60 -KO cell lines established using distinct target sequences (#W60-1-8 and #W60-2-2) and two independent TCTEX1D2 -KO cell lines established using distinct target sequences (#1D2-1-1 and #1D2-2-9) (for characterization of these cell lines, see Supplemental Figure S1), typical data are shown for one of the two established cell lines.…”

WDR60-mediated dynein-2 loading into cilia powers retrograde IFT and transition zone crossing

“…We also show that WDR-60-deficient cilia are at least partially functional in chemotaxis and osmotic tolerance assays, which contrasts with the strong behavioral defects exhibited by the xbx-1(null) mutant, that assembles severely shortened cilia. The mild chemotaxis and osmotic defects that we observe in wdr-60 mutants likely mirror the signaling defects underlying WDR60-associated SRPS (Cossu et al, 2016;Kakar et al, 2018;McInerney-Leo et al, 2013).…”