Various Phenotypes Ranging From OCAI to Normal Pigmentation Caused by Compound Heterozygosity for the Tyrosinase Gene Variant R402Q

Abstract

Introduction: : Mutations in the tyrosinase (TYR) gene, cause oculocutaneous albinism type 1 (OCAI) and autosomal recessive ocular albinism (AROA). About 30 AROA albinos were reported as compound heterozygous (CH) for various "severe" TYR mutations, and the common polymorphism R402Q. Expression studies showed thermolabile tyrosinase activity due to the R402Q mutation. However, CH for various "severe" TYR mutations, and R402Q was reported in normally pigmented parents of albinos with the severe phenotype of OCAIA.

Purpose: : To determine whether R402Q is a pathogenic mutation or common polymorphism.

Methods: : Phenotypic evaluation included description of hair, eye and skin color, presence of nevi and ability to tan. Eye examination included visual acuity, presence of nystagmus, transillumination, visibility of choroidal vessels and hypoplasia of the macula. Blood DNA was PCR amplified followed by restriction digest or sequencing.

Results: : We have screened Israeli Jewish albinos and first degree relatives for the R402Q variant and severe TYR mutations, and identified 23 albinos and 50 self declared normally pigmented relatives who are CH for a severe TYR mutation, and R402Q. Three of these albinos were previously determined as OCAI by histological examination. The entire TYR gene was sequenced in the CH albinos, and no additional TYR mutations were identified. Two TYR mutations - M1V and E294K are always in cis (same allele) with R402Q. Next, we evaluated the phenotype of 20 of the CH albinos, 16 of the normally pigmented CH relatives and their family members. Moderate to mild phenotypes of OCAIB, OCAII and OA, with marked interfamilial variability, were detected in the CH albinos. Some "albinotic" characteristics were observed in all tested "normal" siblings of CH albinos which share the same genotype. This usually includes hypopigmention compared to other family members, and/or in few cases very mild albinotic symptoms upon eye examination. CH parents of OCAIA albinos had normal vision and only few were hypopigmented.

Conclusions: : In most cases CH for severe TYR mutations and R402Q will have normal vision and pigmentation. However, families with a CH albino child are at risk for additional albino (OCA or OA) or hypopigmented sibling with the same genotype. The familial clustering and inter and intrafamilial variability indicate the existence of a modifier of severity.

Keywords: gene/expression • mutations • gene modifiers