RT Journal Article SR Electronic T1 Missense mutations in the WD40 domain of AHI1 cause non-syndromic retinitis pigmentosa JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP jmedgenet-2016-104200 DO 10.1136/jmedgenet-2016-104200 A1 Thanh-Minh T Nguyen A1 Sarah Hull A1 Ronald Roepman A1 L Ingeborgh van den Born A1 Machteld M Oud A1 Erik de Vrieze A1 Lisette Hetterschijt A1 Stef J F Letteboer A1 Sylvia E C van Beersum A1 Ellen A Blokland A1 Helger G Yntema A1 Frans P M Cremers A1 Paul A van der Zwaag A1 Gavin Arno A1 Erwin van Wijk A1 Andrew R Webster A1 Lonneke Haer-Wigman YR 2017 UL http://jmg.bmj.com/content/early/2017/06/24/jmedgenet-2016-104200.abstract AB Background Recent 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 AHI1 variants cause non-syndromic retinitis pigmentosa (RP).Methods Exome sequencing was performed in three probands with RP. The effects of the identified missense variants in AHI1 were 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.Results In 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.Conclusions This report confirms that mutations in AHI1 can underlie autosomal recessive RP. Moreover, it structurally and functionally validates the effect of the RP-associated AHI1 variants on protein function, thus proposing a new genotype–phenotype correlation for AHI1 mutation associated retinal ciliopathies.