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

doi:10.1167/iovs.18-26084

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

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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 adRP and arRP patients were frameshift and/or nonsense variants located far from the 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.

Originele taal-2	Engels
Pagina's (van-tot)	1192-1203
Aantal pagina's	12
Tijdschrift	Investigative Ophthalmology & Visual Science
Volume	60
Nummer van het tijdschrift	4
DOI's	https://doi.org/10.1167/iovs.18-26084
Status	Gepubliceerd - 2019

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Verbakel, S. K., van Huet, R. A. C., den Hollander, A. I., Geerlings, M. J., Kersten, E., Klevering, B. J., Klaver, C. C. W., Plomp, A. S., Wesseling, N. L., Bergen, A. A. B., Nikopoulos, K., Rivolta, C., Ikeda, Y., Sonoda, K.-H., Wada, Y., Boon, C. J. F., Nakazawa, T., Hoyng, C. B., & Nishiguchi, K. M. (2019). Macular Dystrophy and Cone-Rod Dystrophy Caused by Mutations in the RP1 Gene: Extending the RP1 Disease Spectrum. Investigative Ophthalmology & Visual Science, 60(4), 1192-1203. https://doi.org/10.1167/iovs.18-26084

@article{a7d17584650e453d88be7478d54568a6,

title = "Macular Dystrophy and Cone-Rod Dystrophy Caused by Mutations in the RP1 Gene: Extending the RP1 Disease Spectrum",

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 adRP and arRP patients were frameshift and/or nonsense variants located far from the 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.",

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

year = "2019",

doi = "10.1167/iovs.18-26084",

language = "English",

volume = "60",

pages = "1192--1203",

journal = "Investigative Ophthalmology & Visual Science",

issn = "0146-0404",

publisher = "Association for Research in Vision and Ophthalmology Inc.",

number = "4",

}

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, K-H, 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 & Visual Science, vol. 60, nr. 4, blz. 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 et al.
In: Investigative Ophthalmology & Visual Science, Vol. 60, Nr. 4, 2019, blz. 1192-1203.

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

TY - JOUR

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

PY - 2019

Y1 - 2019

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 adRP and arRP patients were frameshift and/or nonsense variants located far from the 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 adRP and arRP patients were frameshift and/or nonsense variants located far from the 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.

U2 - 10.1167/iovs.18-26084

DO - 10.1167/iovs.18-26084

M3 - Article

C2 - 30913292

SN - 0146-0404

VL - 60

SP - 1192

EP - 1203

JO - Investigative Ophthalmology & Visual Science

JF - Investigative Ophthalmology & Visual Science

IS - 4

ER -

Macular Dystrophy and Cone-Rod Dystrophy Caused by Mutations in the RP1 Gene: Extending the RP1 Disease Spectrum

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