Elsevier

Ophthalmology

Volume 119, Issue 12, December 2012, Pages 2616-2621
Ophthalmology

Original article
Identification of an RP1 Prevalent Founder Mutation and Related Phenotype in Spanish Patients with Early-Onset Autosomal Recessive Retinitis

https://doi.org/10.1016/j.ophtha.2012.06.033Get rights and content

Objective

To identify the genetic causes underlying early-onset autosomal recessive retinitis pigmentosa (arRP) in the Spanish population and describe the associated phenotype.

Design

Case series.

Participants

A total of 244 unrelated families affected by early-onset arRP.

Methods

Homozygosity mapping or exome sequencing analysis was performed in 3 families segregating arRP. A mutational screening was performed in 241 additional unrelated families for the p.Ser452Stop mutation. Haplotype analysis also was conducted. Individuals who were homozygotes, double heterozygotes, or carriers of mutations in RP1 underwent an ophthalmic evaluation to establish a genotype–phenotype correlation.

Main Outcome Measures

DNA sequence variants, homozygous regions, haplotypes, best-corrected visual acuity, visual field assessments, electroretinogram responses, and optical coherence tomography images.

Results

Four novel mutations in RP1 were identified. The new mutation p.Ser542Stop was present in 11 of 244 (4.5%) of the studied families. All chromosomes harboring this mutation shared the same haplotype. All patients presented a common phenotype with an early age of onset and a prompt macular degeneration, whereas the heterozygote carriers did not show any signs of retinitis pigmentosa (RP).

Conclusions

p.Ser542Stop is a single founder mutation and the most prevalent described mutation in the Spanish population. It causes early-onset RP with a rapid macular degeneration and is responsible for 4.5% of all cases. Our data suggest that the implication of RP1 in arRP may be underestimated.

Financial Disclosure(s)

The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Section snippets

Patient Recruitment

Patients diagnosed with early-onset RP were recruited from the Fundación Jiménez Díaz Hospital (Madrid, Spain). Diagnostic criteria of early-onset RP included night blindness or peripheral visual loss in the first decade of the life, with poor visual acuity and visual field loss in advanced stages of the disease.

A total of 244 unrelated Spanish families with autosomal recessive or sporadic early-onset RP were selected, because the first symptoms appear in the first decade of life in patients

Materials and Methods

Peripheral blood samples of index cases and their family members were collected in ethylenediaminetetraacetic acid tubes. DNA was extracted from peripheral blood leukocytes with an automated DNA extractor (model BioRobotEZ1; QIAGEN, Hilden, Germany) following the manufacturer's instructions.

Results

Two Spanish families (RP-0056 and RP-1296) were analyzed on a high-resolution SNP array to identify the genetic cause underlying their early-onset arRP. The family RP-0056, comprising 2 affected siblings, showed a high number of homozygous regions (>15) ranging from 1 to 5.6 Mb. In family RP-1296, the 3 affected siblings shared 3 homozygous regions of 1, 1.3, and 7.8 Mb (data not shown). Both families presented a common region: the first and third largest homozygous region located in

Discussion

RP1 is considered a rare causal gene for recessive retinal degeneration.14 This is probably the reason why RP1 is seldom screened in patients with arRP, and no extensive RP1 study for this class of individuals has been reported. We report a single founder mutation; the mutation has been inherited from a common ancestral origin, in the RP1 gene, p.Ser542Stop, which accounts for the 4.5% of the cases and seems to be the most prevalent mutation in our cohort of Spanish patients affected by

References (29)

  • R.K. Ozgül et al.

    Exome sequencing and cis-regulatory mapping identify mutations in MAK, a gene encoding a regulator of ciliary length, as a cause of retinitis pigmentosa

    Am J Hum Genet

    (2011)
  • D.T. Hartong et al.

    Retinitis pigmentosa

    Lancet

    (2006)
  • A.I. Den Hollander et al.

    Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies

    J Clin Invest

    (2010)
  • C. Ayuso et al.

    Retinitis pigmentosa in SpainThe Spanish Multicentric and Multidisciplinary Group for Research into Retinitis Pigmentosa

    Clin Genet

    (1995)
  • A.F. Wright et al.

    Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait

    Nat Rev Genet

    (2010)
  • E.A. Pierce et al.

    Mutations in a gene encoding a new oxygen-regulated photoreceptor protein cause dominant retinitis pigmentosa

    Nat Genet

    (1999)
  • Q. Liu et al.

    Identification and subcellular localization of the RP1 protein in human and mouse photoreceptors

    Invest Ophthalmol Vis Sci

    (2002)
  • L.S. Sullivan et al.

    Mutations in a novel retina-specific gene cause autosomal dominant retinitis pigmentosa

    Nat Genet

    (1999)
  • Q. Liu et al.

    The retinitis pigmentosa 1 protein is a photoreceptor microtubule-associated protein

    J Neurosci

    (2004)
  • T. Yamashita et al.

    Essential and synergistic roles of RP1 and RP1L1 in rod photoreceptor axoneme and retinitis pigmentosa

    J Neurosci

    (2009)
  • Y. Omori et al.

    Negative regulation of ciliary length by ciliary male germ cell-associated kinase (MAK) is required for retinal photoreceptor survival

    Proc Natl Acad Sci U S A

    (2010)
  • B.A. Tucker et al.

    Exome sequencing and analysis of induced pluripotent stem cells identify the cilia-related gene male germ cell-associated kinase (MAK) as a cause of retinitis pigmentosa

    Proc Natl Acad Sci U S A

    (2011)
  • E.M. Stone et al.

    Autosomal recessive retinitis pigmentosa caused by mutations in the MAK gene

    Invest Ophthalmol Vis Sci

    (2011)
  • Cited by (43)

    • Identification of RP1 as the genetic cause of retinitis pigmentosa in a multi-generational pedigree using Extremely Low-Coverage Whole Genome Sequencing (XLC-WGS)

      2023, Gene
      Citation Excerpt :

      The XLC-WGS-based analysis is also three-times cheaper than a non-clinical whole-exome sequencing - WES (∼$300 USD/individual). Most notably, XLC-WGS unveiled the rs779334655 variant as a causal variant for a likely recessive form of RP in our family of interest, consistent with previous independent studies (Avila-Fernandez et al., 2012; Ezquerra-Inchausti et al., 2018; Silva et al., 2020) and supported RP1 as the causal variant for the RP phenotype. The data produced by the XLC-WGS was confirmed by Sanger Sequencing, proving its reliability.

    • Compound dominant-null heterozygosity in a family with RP1-related retinal dystrophy

      2022, American Journal of Ophthalmology Case Reports
      Citation Excerpt :

      Further case reports have largely validated the general principles of this classification,2 however, there are several examples of pathogenic variants that fall within the class II cluster that appear to be recessively inherited.19 A notable example is the p.Ser542Ter founder variant which underlies approximately 5% of autosomal recessive retinitis pigmentosa in a Spanish population, with heterozygous members of these families appearing to be clinically normal.20 Further examples include the p.Ser574Asnfs*8 pathogenic variant which has been found to cause disease in a homozygous state only - including in a case of uniparental disomy of chromosome 8 21 - and p.Asp799*19.

    • Genomic Landscape of Sporadic Retinitis Pigmentosa: Findings from 877 Spanish Cases

      2019, Ophthalmology
      Citation Excerpt :

      As expected, biallelic pathogenic variants in genes carrying AR-inherited defects were the most frequent, and USH2A and CRB1 are the most commonly mutated genes in our cohort, as previously described in another Spanish cohort,13 explaining up to 28% of our characterized patients. As previously described in another sRP Spanish cohort,13 the most prevalent pathogenic alleles were p.(Cys759Phe) in USH2A, known to be one of the most frequent pathogenic variants worldwide,7,29 and the previously reported Spanish founder variants p.(Arg283*), and p.(Ser542*) in CERKL30 and RP1,19 respectively. Approximately 16% of the cases carried pathogenic variants consistent with a non-AR inheritance.

    View all citing articles on Scopus

    Manuscript no. 2012-254.

    Financial Disclosure(s): This study was supported by the following research grants: FIS PI09/90047, FIS PS09/00459, RD09-0076-00101 (Retics Bionbank), the Centre for Biomedical Network Research on Rare Diseases (CIBERER) Intra/07/704.1 and Intra/09/702.1, and Fundaluce 2011. Additional support was provided by the Swiss National Science Foundation (Grant 310030_138346) and the Gebert-Rüf Foundation (Rare Diseases – New Technologies Grant). AA-F is sponsored by the research grant FIS (Sanitary Research Fund) PS09/00459, and MC is sponsored by the CIBERER.

    Both authors contributed equally to this work.

    View full text