RPGRIP1 gene

Overview

Gene (OMIM no.)	RPGRIP1 (#605446)
Function of gene/protein	Protein: retinitis pigmentosa GTPases regulator-interacting protein Localised to the connecting cilium of photoreceptors A scaffold protein required for normal photoreceptor outer segment disk morphogenesis and organisation Anchoring the RPGR protein to the connecting cilium
Clinical phenotype (OMIM phenotype no.)	Autosomal recessive cone-rod dystrophy: Cone-rod dystrophy 13 (#608194) LCA: Leber congenital amaurosis 6 (#613826)
Inheritance	Autosomal recessive
Signs for LCA	Nystagmus Profound visual deficiency Oculodigital sign Photophobia initially Nyctalopia may be reported later on Hypermetropia (<+7.00D) Mild vessel attenuation initially progressing to optic disc pallor, RPE mottling and peripheral pigmentations with retinal degeneration (2nd to 3rd decade of life) Macular atrophy may develop in later stages Keratoconus Cataract
Signs for cone-rod dystrophy	Early onset severe photophobia Dyschromatopsia Variable degree of fundus granularity and macular degeneration Bull’s eye maculopathy seen in one patient
Visual function	LCA: Initial rapid decline in visual function followed by lack of progression (VA 6/60 or worse) Cone-rod dystrophy: Deterioration of central vision and colour blindness from an early age; rapid loss of VA around mid-teens to BCVA 1/60
Systemic features	No extraocular features reported
Key investigations	Full field ERG: Unrecordable or cone-rod dystrophy Pattern ERG FAF to detect areas of RPE atrophy OCT: Relatively preserved foveal outer retinal lamination including the ellipsoid zone (EZ) but progressive EZ loss and outer nuclear layer thinning in the parafoveal and perifoveal regions
Molecular diagnosis	Next generation sequencing Targeted gene panels (retinal) Whole exome sequencing Whole genome sequencing
Management	Ocular Management of LCA Management of cone/cone-rod dystrophy
Therapies under research	Sub-retinal gene therapy in a cone-rod dystrophy dog model
Further information	OMIM

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Additional information

Most of the reported RPGRIP1 variants cause an LCA phenotype, accounting for 5-6% of total LCA cases.^[1] LCA variants tend to cause severely reduced or absent RPGRIP1 protein function (null mutations) while CORD is linked to missense variants that likely retain partial protein function.^[1]

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References

Li T. Leber congenital amaurosis caused by mutations in RPGRIP1. Cold Spring Harb Perspect Med. 2014;5(4). doi:10.1101/cshperspect.a017384
Hanein S, Perrault I, Gerber S, et al. Leber congenital amaurosis: Comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis. Hum Mutat. 2004;23(4):306-317. doi:10.1002/humu.20010
McKibbin M, Ali M, Mohamed MD, et al. Genotype-phenotype correlation for leber congenital amaurosis in Northern Pakistan. Arch Ophthalmol. 2010;128(1):107-113
Khan AO, Abu-Safieh L, Eisenberger T, Bolz HJ, Alkuraya FS. The RPGRIP1-related retinal phenotype in children [published correction appears in Br J Ophthalmol. 2014 Mar;98(3):420]. Br J Ophthalmol. 2013;97(6):760-764
Jacobson SG, Cideciyan AV, Aleman TS, et al. Leber congenital amaurosis caused by an RPGRIP1 mutation shows treatment potential. Ophthalmology. 2007;114(5):895-898
Miyamichi D, Nishina S, Hosono K, et al. Retinal structure in Leber’s congenital amaurosis caused by RPGRIP1 mutations. Hum Genome Var. 2019;6:32
Hameed A, Abid A, Aziz A, Ismail M, Mehdi SQ, Khaliq S. Evidence of RPGRIP1 gene mutations associated with recessive cone-rod dystrophy. J Med Genet. 2003;40(8):616-619. doi:10.1136/jmg.40.8.616

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Updated on November 30, 2020

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