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Evidence that the Ser192Tyr/Arg402Gln in cis Tyrosinase gene haplotype is a disease-causing allele in oculocutaneous albinism type 1B (OCA1B).
- Source :
-
NPJ genomic medicine [NPJ Genom Med] 2022 Jan 13; Vol. 7 (1), pp. 2. Date of Electronic Publication: 2022 Jan 13. - Publication Year :
- 2022
-
Abstract
- Oculocutaneous albinism type 1 (OCA1) is caused by pathogenic variants in the TYR (tyrosinase) gene which encodes the critical and rate-limiting enzyme in melanin synthesis. It is the most common OCA subtype found in Caucasians, accounting for ~50% of cases worldwide. The apparent 'missing heritability' in OCA is well described, with ~25-30% of clinically diagnosed individuals lacking two clearly pathogenic variants. Here we undertook empowered genetic studies in an extensive multigenerational Amish family, alongside a review of previously published literature, a retrospective analysis of in-house datasets, and tyrosinase activity studies. Together this provides irrefutable evidence of the pathogenicity of two common TYR variants, p.(Ser192Tyr) and p.(Arg402Gln) when inherited in cis alongside a pathogenic TYR variant in trans. We also show that homozygosity for the p.(Ser192Tyr)/p.(Arg402Gln) TYR haplotype results in a very mild, but fully penetrant, albinism phenotype. Together these data underscore the importance of including the TYR p.(Ser192Tyr)/p.(Arg402Gln) in cis haplotype as a pathogenic allele causative of OCA, which would likely increase molecular diagnoses in this missing heritability albinism cohort by 25-50%.<br /> (© 2022. The Author(s).)
Details
- Language :
- English
- ISSN :
- 2056-7944
- Volume :
- 7
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- NPJ genomic medicine
- Publication Type :
- Academic Journal
- Accession number :
- 35027574
- Full Text :
- https://doi.org/10.1038/s41525-021-00275-9