DNA variations in oculocutaneous albinism: an updated mutation list and current outstanding issues in molecular diagnostics

Abstract

Oculocutaneous albinism (OCA) is a rare genetic disorder of melanin synthesis that results in hypopigmented hair, skin, and eyes. There are four types of OCA caused by mutations in TYR (OCA-1), OCA2 (OCA-2), TYRP1 (OCA-3), or SLC45A2 (OCA-4). Here we report 22 novel mutations in the OCA genes; 14 from a cohort of 61 patients seen as part of the NIH OCA Natural History Study and eight from a prior study at the University of Minnesota. We also include a comprehensive list of almost 600 previously reported OCA mutations along with ethnicity information, carrier frequencies, and in silico pathogenicity predictions as a supplement. In addition to discussing the clinical and molecular features of OCA, we address the cases of apparent missing heritability. In our cohort, 26% of patients did not have two mutations in a single OCA gene. We demonstrate the utility of multiple detection methods to reveal mutations missed by Sanger sequencing. Finally, we review the TYR p.R402Q temperature-sensitive variant and confirm its association with cases of albinism with only one identifiable TYR mutation.

Figure 1

Variable phenotype of albinism. Pigmentation differences are evident in the hair, the iris (assessed by transillumination), and melanocyte pellets between persons with partial and complete albinism.

Figure 2

Homology modeling of tyrosinase, TYRP1, and SLC45A2. All three structures are shown with their predicted orientation in the melanosomal membrane (Figure 2A). The novel mutations TYR p.A490D, TYRP1 p.A24T, and SLC45A2 p.L60R mutations are indicated within the respective structures (Figure 2A). Panels B and C reveal the functional domains and the copper coordinating center of tyrosinase, respectively. Positions of the novel missense mutations found in TYR (Figure 2D) and SLC45A2 (Figure 2E).