Screening of TYR, OCA2, GPR143, and MC1R in patients with congenital nystagmus, macular hypoplasia, and fundus hypopigmentation indicating albinism.

BACKGROUND: A broad spectrum of pigmentation of the skin and hair is found among patients diagnosed with ocular albinism (OA) and oculocutaneous albinism (OCA). Even though complexion is variable, three ocular features, i.e., hypopigmentation of the fundus, hypoplasia of the macula, and nystagmus, are classical pathological findings in these patients. We screened 172 index patients with a clinical diagnosis of OA or OCA based on the classical findings, to evaluate the frequency of sequence variants in tyrosinase (TYR), P-gene, P-protein (OCA2), and the G-protein-coupled receptor 143 gene, OA1 (GPR143). In addition, we investigated the association of sequence variants in the melanocortin receptor 1 gene (MC1R) and OCA2. METHODS: Pigmentation of the hair, skin, iris, and fundus were included in the evaluation of OCA and OA. Male OA patients showing X-linked inheritance were screened for GPR143. Females showing OA without family history were regarded as representing autosomal recessive OA (OA3). Direct sequencing was applied to PCR products showing aberrant single-strand conformation polymorphism-banding patterns. RESULTS: Fifty-seven male index patients were screened for OA. We identified 16 potentially pathogenic sequence variations in GPR143 (10 novel) in 22 males. In TYR, we identified 23 (7 novel), and in OCA2 28 (11 novel) possibly pathogenic variants. Variants on both alleles were identified in TYR or OCA2 in 29/79 OCA patients and 14/71 OA patients. Sequence changes in TYR were identified almost exclusively in OCA patients, while sequence changes in OCA2 occurred in OCA and OA patients. MC1R sequencing was performed in 47 patients carrying mutations in OCA2 and revealed MC1R mutations in 42 of them. CONCLUSIONS: TYR gene mutations have a more severe effect on pigmentation than mutations in OCA2 and the GPR143 gene. Nevertheless, mutations in these genes affect the development of visual function either directly or by interaction with other genes like MC1R, which can be deduced from a frequent association of MC1R variants with p.R305W or p.R419Q in OCA2.

Mutation analysis in a family with oculocutaneous albinism manifesting in the same generation of three branches.

PURPOSE: To elucidate the molecular basis of oculocutaneous albinism with variable expressivity in a family from The Netherlands in which no consanguinity was reported. METHODS: Three affected family members were screened for mutations in tyrosinase (TYR) and the pink-eye-dilution gene (P) by using SSCP. The melanocortin receptor gene (MC1R) and amplimers of P showing an aberrant banding pattern in SSCP were analyzed by direct sequencing. All participants underwent ophthalmologic examination including funduscopy, and visually evoked potentials were recorded in two cases. RESULTS: The pedigree had three branches A, B, and C. We identified three mutations in P (V443I, N476S, C793F) that cause a compound heterozygous situation in cases from branch A (N476S/C793F) and B (V443I/C793F), who showed oculocutaneous albinism. Hair and skin color followed the light Nordic complexion that was also present in other affected and unaffected members of this family. Descendants of branches A and B showed light complexion with iris translucency and peripheral fundus hypopigmentation independent from the genotype identified. A single descendant had red hair, carrying a well known compound MC1R mutation combination for red hair color and a single heterozygous P mutation. CONCLUSIONS: P mutations underlie oculocutaneous albinism in this family. Two known mutations in MC1R caused red hair color in one family member. No modifier effect of MC1R on P mutations could be deduced from the results of this study.