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Anika Nanda, Michelle McClements, Morag Shanks, Robert MacLaren; The spectrum of RP1 mutations confirms a dominant negative disease mechanism. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2329.
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© ARVO (1962-2015); The Authors (2016-present)
Mutations in the photoreceptor gene RP1 may lead to recessive or dominantly inherited retinitis pigmentosa (RP). Since the dominantly inherited phenotype is considerably milder than recessive cases, it raises the possibility that it could arise by haploinsufficiency. We therefore assessed a cohort of RP patients with confirmed mutations in RP1 in order to examine the genetic basis of the mutations in more detail.
A retrospective review of 14 patients, aged between 36 and 84, identified with RP1 mutations confirmed by Sanger genetic sequencing. All patients underwent full ophthalmic examination, including visual acuities with auto fluorescence imaging and optical coherence tomography.
Two patients had homozygous mutations in RP1 and had severe early onset retinal degeneration (p.Glu1526X and p.Ser486fs). Twelve patients had dominantly inherited retinitis pigmentosa presenting in adult life with a rod-cone dystrophy phenotype. All mutations were in exon 4 of the RP1 gene and would be predicted to generate truncated RP1 protein as follows: p.Leu866Lysfs*7x2, p.Ile725Argfs*6, p.Gln917*, p.Ser734*x2, p.Leu762Tyrfs*17x2, p.Arg677*, p.Arg872Thrfs*2x2 and p.Gln679*. No dominantly inherited mutations were identified in upstream exons 1-3.
The spectrum of RP1 mutations in dominantly inherited RP is confined to exon 4 from which truncated transcripts would be predicted to generate mutant protein. The finding of exon 4 mutations as a cause of severe RP may be indicative of homozygous dominant mutations that could make genetic counselling difficult.
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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