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Susanne Roosing, Suzanne E. de Bruijn, Sanne Kirsten Verbakel, Hannie Kremer, L. Ingeborgh van den Born, Carel C B Hoyng, Frans P Cremers; Homozygous mutations in KIAA1549, encoding a ciliary protein, cause autosomal recessive retinitis pigmentosa.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2321.
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© ARVO (1962-2015); The Authors (2016-present)
Retinitis pigmentosa (RP) shows substantial genetic heterogeneity. It has been estimated that in 63% of RP cases a genetic explanation can be found using whole exome sequencing (WES), which is the most widely applied method for disease gene identification. The purpose of this study is to identify novel causative genes for inherited retinal diseases, and to gain further insight into the function of identified genes and their role in the pathogenesis of RP.
To identify causative variants in individuals with genetically unexplained retinal disease, we included one consanguineous Iranian family with two affected siblings (Family A) and one isolated Dutch case (Family B) in this study. For both probands WES was performed, and clinical analysis including visual acuity and dilated fundus examination, fundus photography, fundus autofluorescence imaging, optical coherence tomography, Goldmann perimetry, and electroretinography was performed to determine the phenotypic characteristics. In addition, mRNA expression and protein localization studies were performed to obtain insights into the function of KIAA1549 in photoreceptors.
Affected individuals showed clinical features of classical RP. Through analysis of the filtered WES data, based on their population allele frequency, conservation score and the CADD deleteriousness score, we identified homozygous missense and frameshift variants in these families in KIAA1549. A second affected person of Family A also carried the frameshift variant in a homozygous state. KIAA1549 was found to localize in the connecting cilium of the photoreceptor cells and the synapses of the mouse retina. Both pathogenic variants affect the long transcript of KIAA1549 which encodes a 1950-aa protein. While the shorter transcript encodes a protein of 945 aa and shows high retinal expression, it is only affected by the variant found in Family B.
In this study we identified homozygous KIAA1549 variants in two RP families. A homozygous protein-truncating KIAA1549 variant was reported earlier in an isolated RP case by Abu-Safieh et al. (Genome research, 23(2):236-237, 2013). Our results thereby strengthen the candidacy for KIAA1549 to be implicated in autosomal recessive RP. Moreover, we show localization of KIAA1549 to the connecting cilium of photoreceptors as well as the synapses.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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