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- Title
Evidence that the Ser192Tyr/Arg402Gln in cis Tyrosinase gene haplotype is a disease-causing allele in oculocutaneous albinism type 1B (OCA1B).
- Authors
Lin, Siying; Sanchez-Bretaño, Aida; Leslie, Joseph S.; Williams, Katie B.; Lee, Helena; Thomas, N. Simon; Callaway, Jonathan; Deline, James; Ratnayaka, J. Arjuna; Baralle, Diana; Schmitt, Melanie A.; Norman, Chelsea S.; Hammond, Sheri; Harlalka, Gaurav V.; Ennis, Sarah; Cross, Harold E.; Wenger, Olivia; Crosby, Andrew H.; Baple, Emma L.; Self, Jay E.
- 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%.
- Subjects
PHENOL oxidase; HAPLOTYPES; ALLELES; PATHOGENIC bacteria; HERITABILITY
- Publication
NPJ Genomic Medicine, 2022, Vol 7, Issue 1, p1
- ISSN
2056-7944
- Publication type
Article
- DOI
10.1038/s41525-021-00275-9