WDR19: an ancient, retrograde, intraflagellar ciliary protein is mutated in autosomal recessive retinitis pigmentosa and in Senior-Loken syndrome

Abstract

Autosomal recessive retinitis pigmentosa (arRP) is a clinically and genetically heterogeneous retinal disease that causes blindness. Our purpose was to identify the causal gene, describe the phenotype and delineate the mutation spectrum in a consanguineous Quebec arRP family. We performed Arrayed Primer Extension (APEX) technology to exclude ∼500 arRP mutations in ∼20 genes. Homozygosity mapping [single nucleotide polymorphism (SNP) genotyping] identified 10 novel significant homozygous regions. We performed next generation sequencing and whole exome capture. Sanger sequencing provided cosegregation. We screened another 150 retinitis pigmentosa (RP) and 200 patients with Senior-Løken Syndrome (SLS). We identified a novel missense mutation in WDR19, c.2129T>C which lead to a p.Leu710Ser. We found the same mutation in a second Quebec arRP family. Interestingly, two of seven affected members of the original family developed 'sub-clinical' renal cysts. We hypothesized that more severe WDR19 mutations may lead to severe ciliopathies and found seven WDR19 mutations in five SLS families. We identified a new gene for both arRP and SLS. WDR19 is a ciliary protein associated with the intraflagellar transport machinery. We are currently investigating the full extent of the mutation spectrum. Our findings are crucial in expanding the understanding of childhood blindness and identifying new genes.

Keywords: IFT-A; IFT144; Senior-Løken syndrome; WDR19; childhood blindness; nephronophtisis; photoreceptors; retinal degeneration; retinitis pigmentosa.

Fig. 1

(a) Family A pedigree. (b) Retinal photo showing an atrophic maculopathy and severe narrowing of the blood vessels and temporal pallor of the optic nerve head. (c) Fundus autofluorescence showing the ‘bear claw’ maculopathy and hypo-fluorescence in the fovea. (d) Optical coherence tomography of the macula showing extensive loss of the inner segment/outer segment junctions and photoreceptors, with inner retinal changes, retinal thinning and foveal debris. (e) Renal ultrasound showing the renal cyst of the probands of family A.

Fig. 2

(a) Gene and protein structure of WDR19 and IFT144, showing the protein domains and the positions of all the mutations found in this study and in Bredrup et al. showing that most mutations are in protein domains except the p. L710S mutation. (b) Conservation of the Leucine at position 710 in IFT144 (WDR19) among species. (c) Sanger sequencing results of the WDR19 mutations in Family A. (d) Sanger sequencing results of the WDR19 mutations in Senior-Loken syndrome patients.

Fig. 3

(a) Family B pedigree. (b) Retinal photo showing an atrophic maculopathy and severe narrowing of the blood vessels and temporal pallor of the optic nerve head. (c) Peripheral bone spicules, extensive. (d) Fundus autofluorescence showing the ‘bear claw’ maculopathy and the hypofluorescence in the fovea. (e) Optical coherence tomography of the macula showing extensive loss of the inner segment/outer segment junctions and photoreceptors, with inner retinal changes, retinal thinning and foveal debris.