Macular dystrophy and cone-rod dystrophy caused by mutations in the RP1 gene: Extending the RP1 disease spectrum

Sanne K. Verbakel, Ramon A.C. Van Huet, Anneke I. Den Hollander, Maartje J. Geerlings, Eveline Kersten, B. Jeroen Klevering, Caroline C.W. Klaver, Astrid S. Plomp, Nieneke L. Wesseling, Arthur A.B. Bergen, Konstantinos Nikopoulos, Carlo Rivolta, Yasuhiro Ikeda, Koh Hei Sonoda, Yuko Wada, Camiel J.F. Boon, Toru Nakazawa, Carel B. Hoyng, Koji M. Nishiguchi

Research output: Contribution to journalArticle

Abstract

PURPOSE. To describe the clinical and genetic spectrum of RP1-associated retinal dystrophies. METHODS. In this multicenter case series, we included 22 patients with RP1-associated retinal dystrophies from 19 families from The Netherlands and Japan. Data on clinical characteristics, visual acuity, visual field, ERG, and retinal imaging were extracted from medical records over a mean follow-up of 8.1 years. RESULTS. Eleven patients were diagnosed with autosomal recessive macular dystrophy (arMD) or autosomal recessive cone-rod dystrophy (arCRD), five with autosomal recessive retinitis pigmentosa (arRP), and six with autosomal dominant RP (adRP). The mean age of onset was 40.3 years (range 14–56) in the patients with arMD/arCRD, 26.2 years (range 18–40) in adRP, and 8.8 years (range 5–12) in arRP patients. All patients with arMD/arCRD carried either the hypomorphic p.Arg1933* variant positioned close to the C-terminus (8 of 11 patients) or a missense variant in exon 2 (3 of 11 patients), compound heterozygous with a likely deleterious frameshift or nonsense mutation, or the p.Gln1916* variant. In contrast, all mutations identified in adRPand arRP patients were frame shift and/or nonsense variants located far fromthe C -terminus. CONCLUSIONS. Mutations in the RP1 gene are associated with a broad spectrum of progressive retinal dystrophies. In addition to adRP and arRP, our study provides further evidence that arCRD and arMD are RP1-associated phenotypes as well. The macular involvement in patients with the hypomorphic RP1 variant suggests that macular function may remain compromised if expression levels of RP1 do not reach adequate levels after gene augmentation therapy.

Original languageEnglish
Pages (from-to)1192-1203
Number of pages12
JournalInvestigative Ophthalmology and Visual Science
Volume60
Issue number4
DOIs
Publication statusPublished - Mar 2019

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Macular Degeneration
Mutation
Retinitis Pigmentosa
Retinal Dystrophies
Genes
Cone-Rod Dystrophies
Frameshift Mutation
Nonsense Codon
Visual Fields
Age of Onset
Genetic Therapy
Netherlands
Visual Acuity
Medical Records
Exons
Japan
Phenotype

All Science Journal Classification (ASJC) codes

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Verbakel, S. K., Van Huet, R. A. C., Den Hollander, A. I., Geerlings, M. J., Kersten, E., Klevering, B. J., ... Nishiguchi, K. M. (2019). Macular dystrophy and cone-rod dystrophy caused by mutations in the RP1 gene: Extending the RP1 disease spectrum. Investigative Ophthalmology and Visual Science, 60(4), 1192-1203. https://doi.org/10.1167/iovs.18-26084

Macular dystrophy and cone-rod dystrophy caused by mutations in the RP1 gene : Extending the RP1 disease spectrum. / Verbakel, Sanne K.; Van Huet, Ramon A.C.; Den Hollander, Anneke I.; Geerlings, Maartje J.; Kersten, Eveline; Klevering, B. Jeroen; Klaver, Caroline C.W.; Plomp, Astrid S.; Wesseling, Nieneke L.; Bergen, Arthur A.B.; Nikopoulos, Konstantinos; Rivolta, Carlo; Ikeda, Yasuhiro; Sonoda, Koh Hei; Wada, Yuko; Boon, Camiel J.F.; Nakazawa, Toru; Hoyng, Carel B.; Nishiguchi, Koji M.

In: Investigative Ophthalmology and Visual Science, Vol. 60, No. 4, 03.2019, p. 1192-1203.

Research output: Contribution to journalArticle

Verbakel, SK, Van Huet, RAC, Den Hollander, AI, Geerlings, MJ, Kersten, E, Klevering, BJ, Klaver, CCW, Plomp, AS, Wesseling, NL, Bergen, AAB, Nikopoulos, K, Rivolta, C, Ikeda, Y, Sonoda, KH, Wada, Y, Boon, CJF, Nakazawa, T, Hoyng, CB & Nishiguchi, KM 2019, 'Macular dystrophy and cone-rod dystrophy caused by mutations in the RP1 gene: Extending the RP1 disease spectrum', Investigative Ophthalmology and Visual Science, vol. 60, no. 4, pp. 1192-1203. https://doi.org/10.1167/iovs.18-26084
Verbakel, Sanne K. ; Van Huet, Ramon A.C. ; Den Hollander, Anneke I. ; Geerlings, Maartje J. ; Kersten, Eveline ; Klevering, B. Jeroen ; Klaver, Caroline C.W. ; Plomp, Astrid S. ; Wesseling, Nieneke L. ; Bergen, Arthur A.B. ; Nikopoulos, Konstantinos ; Rivolta, Carlo ; Ikeda, Yasuhiro ; Sonoda, Koh Hei ; Wada, Yuko ; Boon, Camiel J.F. ; Nakazawa, Toru ; Hoyng, Carel B. ; Nishiguchi, Koji M. / Macular dystrophy and cone-rod dystrophy caused by mutations in the RP1 gene : Extending the RP1 disease spectrum. In: Investigative Ophthalmology and Visual Science. 2019 ; Vol. 60, No. 4. pp. 1192-1203.
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abstract = "PURPOSE. To describe the clinical and genetic spectrum of RP1-associated retinal dystrophies. METHODS. In this multicenter case series, we included 22 patients with RP1-associated retinal dystrophies from 19 families from The Netherlands and Japan. Data on clinical characteristics, visual acuity, visual field, ERG, and retinal imaging were extracted from medical records over a mean follow-up of 8.1 years. RESULTS. Eleven patients were diagnosed with autosomal recessive macular dystrophy (arMD) or autosomal recessive cone-rod dystrophy (arCRD), five with autosomal recessive retinitis pigmentosa (arRP), and six with autosomal dominant RP (adRP). The mean age of onset was 40.3 years (range 14–56) in the patients with arMD/arCRD, 26.2 years (range 18–40) in adRP, and 8.8 years (range 5–12) in arRP patients. All patients with arMD/arCRD carried either the hypomorphic p.Arg1933* variant positioned close to the C-terminus (8 of 11 patients) or a missense variant in exon 2 (3 of 11 patients), compound heterozygous with a likely deleterious frameshift or nonsense mutation, or the p.Gln1916* variant. In contrast, all mutations identified in adRPand arRP patients were frame shift and/or nonsense variants located far fromthe C -terminus. CONCLUSIONS. Mutations in the RP1 gene are associated with a broad spectrum of progressive retinal dystrophies. In addition to adRP and arRP, our study provides further evidence that arCRD and arMD are RP1-associated phenotypes as well. The macular involvement in patients with the hypomorphic RP1 variant suggests that macular function may remain compromised if expression levels of RP1 do not reach adequate levels after gene augmentation therapy.",
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T1 - Macular dystrophy and cone-rod dystrophy caused by mutations in the RP1 gene

T2 - Extending the RP1 disease spectrum

AU - Verbakel, Sanne K.

AU - Van Huet, Ramon A.C.

AU - Den Hollander, Anneke I.

AU - Geerlings, Maartje J.

AU - Kersten, Eveline

AU - Klevering, B. Jeroen

AU - Klaver, Caroline C.W.

AU - Plomp, Astrid S.

AU - Wesseling, Nieneke L.

AU - Bergen, Arthur A.B.

AU - Nikopoulos, Konstantinos

AU - Rivolta, Carlo

AU - Ikeda, Yasuhiro

AU - Sonoda, Koh Hei

AU - Wada, Yuko

AU - Boon, Camiel J.F.

AU - Nakazawa, Toru

AU - Hoyng, Carel B.

AU - Nishiguchi, Koji M.

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N2 - PURPOSE. To describe the clinical and genetic spectrum of RP1-associated retinal dystrophies. METHODS. In this multicenter case series, we included 22 patients with RP1-associated retinal dystrophies from 19 families from The Netherlands and Japan. Data on clinical characteristics, visual acuity, visual field, ERG, and retinal imaging were extracted from medical records over a mean follow-up of 8.1 years. RESULTS. Eleven patients were diagnosed with autosomal recessive macular dystrophy (arMD) or autosomal recessive cone-rod dystrophy (arCRD), five with autosomal recessive retinitis pigmentosa (arRP), and six with autosomal dominant RP (adRP). The mean age of onset was 40.3 years (range 14–56) in the patients with arMD/arCRD, 26.2 years (range 18–40) in adRP, and 8.8 years (range 5–12) in arRP patients. All patients with arMD/arCRD carried either the hypomorphic p.Arg1933* variant positioned close to the C-terminus (8 of 11 patients) or a missense variant in exon 2 (3 of 11 patients), compound heterozygous with a likely deleterious frameshift or nonsense mutation, or the p.Gln1916* variant. In contrast, all mutations identified in adRPand arRP patients were frame shift and/or nonsense variants located far fromthe C -terminus. CONCLUSIONS. Mutations in the RP1 gene are associated with a broad spectrum of progressive retinal dystrophies. In addition to adRP and arRP, our study provides further evidence that arCRD and arMD are RP1-associated phenotypes as well. The macular involvement in patients with the hypomorphic RP1 variant suggests that macular function may remain compromised if expression levels of RP1 do not reach adequate levels after gene augmentation therapy.

AB - PURPOSE. To describe the clinical and genetic spectrum of RP1-associated retinal dystrophies. METHODS. In this multicenter case series, we included 22 patients with RP1-associated retinal dystrophies from 19 families from The Netherlands and Japan. Data on clinical characteristics, visual acuity, visual field, ERG, and retinal imaging were extracted from medical records over a mean follow-up of 8.1 years. RESULTS. Eleven patients were diagnosed with autosomal recessive macular dystrophy (arMD) or autosomal recessive cone-rod dystrophy (arCRD), five with autosomal recessive retinitis pigmentosa (arRP), and six with autosomal dominant RP (adRP). The mean age of onset was 40.3 years (range 14–56) in the patients with arMD/arCRD, 26.2 years (range 18–40) in adRP, and 8.8 years (range 5–12) in arRP patients. All patients with arMD/arCRD carried either the hypomorphic p.Arg1933* variant positioned close to the C-terminus (8 of 11 patients) or a missense variant in exon 2 (3 of 11 patients), compound heterozygous with a likely deleterious frameshift or nonsense mutation, or the p.Gln1916* variant. In contrast, all mutations identified in adRPand arRP patients were frame shift and/or nonsense variants located far fromthe C -terminus. CONCLUSIONS. Mutations in the RP1 gene are associated with a broad spectrum of progressive retinal dystrophies. In addition to adRP and arRP, our study provides further evidence that arCRD and arMD are RP1-associated phenotypes as well. The macular involvement in patients with the hypomorphic RP1 variant suggests that macular function may remain compromised if expression levels of RP1 do not reach adequate levels after gene augmentation therapy.

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