Missense mutations in the WD40 domain of AHI1cause non-syndromic retinitis pigmentosa

BackgroundRecent findings suggesting that Abelson helper integration site 1(AHI1) is involved in non-syndromic retinal disease have been debated, as the functional significance of identified missense variants was uncertain. We assessed whether AHI1variants cause non-syndromic retinitis pigmentosa (RP).MethodsExome sequencing was performed in three probands with RP. The effects of the identified missense variants in AHI1were predicted by three-dimensional structure homology modelling. Ciliary parameters were evaluated in patient’s fibroblasts, and recombinant mutant proteins were expressed in ciliated retinal pigmented epithelium cells.ResultsIn the three patients with RP, three sets of compound heterozygous variants were detected in AHI1(c.2174G>A; p.Trp725* and c.2258A>T; p.Asp753Val, c.660delC; p.Ser221Glnfs*10 and c.2090C>T; p.Pro697Leu, c.2087A>G; p.His696Arg and c.2429C>T; p.Pro810Leu). All four missense variants were present in the conserved WD40 domain of Jouberin, the ciliary protein encoded by AHI1, with variable predicted implications for the domain structure. No significant changes in the percentage of ciliated cells, nor in cilium length or intraflagellar transport were detected. However, expression of mutant recombinant Jouberin in ciliated cells showed a significantly decreased enrichment at the ciliary base.ConclusionsThis report confirms that mutations in AHI1can underlie autosomal recessive RP. Moreover, it structurally and functionally validates the effect of the RP-associated AHI1variants on protein function, thus proposing a new genotype–phenotype correlation for AHI1mutation associated retinal ciliopathies.