Anika Nanda1, Michelle E McClements2, Penny Clouston3, Morag E Shanks3, Robert E MacLaren4. 1. Oxford University Hospitals NHS Foundation Trust and NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, United Kingdom. Electronic address: anika.nanda@ouh.nhs.uk. 2. Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, United Kingdom. 3. Oxford University Hospitals NHS Foundation Trust, Oxford Medical Genetics Laboratories, The Churchill Hospital, Oxford, United Kingdom. 4. Oxford University Hospitals NHS Foundation Trust and NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, United Kingdom; Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, United Kingdom.
Abstract
PURPOSE: Mutations in the photoreceptor gene RP1 lead to recessive or dominantly inherited retinitis pigmentosa (RP). Since the dominantly inherited phenotype is generally milder than recessive cases, it raises the possibility that it could arise by haploinsufficiency; however, most mutations are in the terminal exon 4, which would be predicted to generate truncated proteins. We therefore assessed a cohort of RP patients with confirmed mutations in RP1 to examine the genetic basis of the exon 4 mutations. DESIGN: Observational case series. METHODS: A retrospective review of 15 patients, aged between 36 and 84, with RP1 mutations in exon 4 confirmed by Sanger sequencing. All patients underwent full ophthalmic examination. RESULTS: Two patients had homozygous mutations in RP1, p.(Glu1526*) and p.(Ser486fs), and presented with severe early-onset retinal degeneration. Their first-degree relatives were unaffected. Thirteen patients had dominantly inherited RP presenting in adult life with a rod-cone dystrophy phenotype. Four novel mutations were identified. All mutations were predicted to produce truncated RP1 protein of variable lengths, as follows: p.(Arg677*), p.(Gln679*), p.(Leu722*), p.(Ile725Argfs*6), p.(Ser734*)x2, p.(Leu762Tyrfs*17)x2, p.(Leu866Lysfs*7)x2, p.(Arg872Thrfs*2)x2, and p.(Gln917*). CONCLUSION: The RP1 protein with a predicted length between 677 and 917 amino acids seems to have a dominant negative effect, whereas proteins shorter (486 amino acids) or longer than this (1526 amino acids) lead to a more severe phenotype, but only in homozygous individuals. Since mutations at various points along exon 4 have divergent consequences, genetic testing alone may be insufficient for counseling, but recessive inheritance should be considered likely in severe early-onset cases.
PURPOSE: Mutations in the photoreceptor gene RP1 lead to recessive or dominantly inherited retinitis pigmentosa (RP). Since the dominantly inherited phenotype is generally milder than recessive cases, it raises the possibility that it could arise by haploinsufficiency; however, most mutations are in the terminal exon 4, which would be predicted to generate truncated proteins. We therefore assessed a cohort of RP patients with confirmed mutations in RP1 to examine the genetic basis of the exon 4 mutations. DESIGN: Observational case series. METHODS: A retrospective review of 15 patients, aged between 36 and 84, with RP1 mutations in exon 4 confirmed by Sanger sequencing. All patients underwent full ophthalmic examination. RESULTS: Two patients had homozygous mutations in RP1, p.(Glu1526*) and p.(Ser486fs), and presented with severe early-onset retinal degeneration. Their first-degree relatives were unaffected. Thirteen patients had dominantly inherited RP presenting in adult life with a rod-cone dystrophy phenotype. Four novel mutations were identified. All mutations were predicted to produce truncated RP1 protein of variable lengths, as follows: p.(Arg677*), p.(Gln679*), p.(Leu722*), p.(Ile725Argfs*6), p.(Ser734*)x2, p.(Leu762Tyrfs*17)x2, p.(Leu866Lysfs*7)x2, p.(Arg872Thrfs*2)x2, and p.(Gln917*). CONCLUSION: The RP1 protein with a predicted length between 677 and 917 amino acids seems to have a dominant negative effect, whereas proteins shorter (486 amino acids) or longer than this (1526 amino acids) lead to a more severe phenotype, but only in homozygous individuals. Since mutations at various points along exon 4 have divergent consequences, genetic testing alone may be insufficient for counseling, but recessive inheritance should be considered likely in severe early-onset cases.
Authors: Manon H C A Peeters; Mubeen Khan; Anoek A M B Rooijakkers; Timo Mulders; Lonneke Haer-Wigman; Camiel J F Boon; Caroline C W Klaver; L Ingeborgh van den Born; Carel B Hoyng; Frans P M Cremers; Anneke I den Hollander; Claire-Marie Dhaenens; Rob W J Collin Journal: Hum Mutat Date: 2021-09-20 Impact factor: 4.700
Authors: Rachel M Huckfeldt; Florin Grigorian; Emily Place; Jason I Comander; Demetrios Vavvas; Lucy H Young; Paul Yang; Maria Shurygina; Eric A Pierce; Mark E Pennesi Journal: Mol Vis Date: 2020-06-03 Impact factor: 2.367