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Re-evaluation casts doubt on the pathogenicity of homozygous USH2A p.C759F.
- Source :
-
American journal of medical genetics. Part A [Am J Med Genet A] 2015 Jul; Vol. 167 (7), pp. 1597-600. Date of Electronic Publication: 2015 Mar 30. - Publication Year :
- 2015
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Abstract
- Mutations in USH2A are a common cause of Retinitis Pigmentosa (RP). Among the most frequently reported USH2A variants, c.2276G>T (p.C759F) has been found in both affected and healthy individuals. The pathogenicity of this variant remains controversial since it was detected in homozygosity in two healthy siblings of a Spanish family (S23), eleven years ago. The fact that these individuals remain asymptomatic today, prompted us to study the presence of other pathogenic variants in this family using targeted resequencing of 26 retinal genes in one of the affected individuals. This approach allowed us to identify one novel pathogenic homozygous mutation in exon 13 of PDE6B (c.1678C>T; p.R560C). This variant cosegregated with the disease and was absent in 200 control individuals. Remarkably, the identified variant in PDE6B corresponds to the mutation responsible of the retinal degeneration in the naturally occurring rd10 mutant mice. To our knowledge, this is the first report of the identification of the rd10 mice mutation in a RP family. These findings, together with a review of the literature, support the hypothesis that homozygous p.C759F mutations are not pathogenic and led us to exclude the implication of p.C759F in the RP of family S23. Our results indicate the need of re-evaluating all families genetically diagnosed with this mutation.<br /> (© 2015 Wiley Periodicals, Inc.)
- Subjects :
- Base Sequence
Extracellular Matrix Proteins adverse effects
Gene Library
Humans
Molecular Sequence Data
Mutation, Missense genetics
Pedigree
Retinitis Pigmentosa pathology
Sequence Analysis, DNA
Spain
Cyclic Nucleotide Phosphodiesterases, Type 6 genetics
Extracellular Matrix Proteins genetics
Retinitis Pigmentosa genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1552-4833
- Volume :
- 167
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- American journal of medical genetics. Part A
- Publication Type :
- Academic Journal
- Accession number :
- 25823529
- Full Text :
- https://doi.org/10.1002/ajmg.a.37003