Oculocutaneous albinism in a patient with an OCA2 variant: molecular and clinical insights

Abstract

Background: Albinism is a rare genetic condition characterized by hypopigmentation of the skin, hair, and eyes, as well as visual impairments. Oculocutaneous albinism type 2 (OCA2) is commonly associated with variants in the OCA2 gene, which encodes a protein critical for melanosomal pH regulation and melanin biosynthesis. Exome sequencing, validated by Sanger sequencing, was employed to investigate the genetic basis of albinism in a consanguineous Iranian family. Bioinformatics analyses and structural modeling were conducted to assess the pathogenicity and impact of the detected variant.

Case presentation: A 27-year-old male from a consanguineous Iranian family presented with features of oculocutaneous albinism, including white hair, blue eyes, strabismus, sun-sensitive skin, reduced visual acuity, and significant photophobia, resulting in functional limitations in bright environments. Genetic analysis identified a novel homozygous missense variant in the OCA2 gene, NM_000275.3:c.1274T>G (p.Met425Arg), located in exon 13. The genomic coordinates of the variant are chr15:g.27985154A>C (GRCh38/hg38). In silico tools classified the variant as likely pathogenic based on its evolutionary conservation, absence in population databases, and structural modeling predictions. Segregation analysis confirmed autosomal recessive inheritance, with both parents being heterozygous carriers.

Conclusion: The identified OCA2 variant, c.1274T>G; p.Met425Arg, disrupts protein function, impairing melanosomal activity and melanin biosynthesis. This study underscores the importance of genetic analysis in characterizing OCA2 variants and highlights the need for further exploration of molecular mechanisms and phenotypic variability in OCA2-related albinism to improve diagnosis and counseling.

Keywords: OCA2 gene; anexome-sequencing; genetic diagnosis; oculocutaneous albinism; variant.

Figure 1.

(A) Pedigree of the family with albinism. Squares represent male individuals, circles represent female individuals, the black square represents the affected male patient, slashes indicate deceased individuals, and the arrow denotes the proband. Consanguineous marriage is indicated by double lines, suggesting a recessive inheritance pattern. (B) The proband with albinism shows characteristic features, including white hair, blue eyes, and right-eye deviation indicative of strabismus. Published with the patient’s written informed consent.

Figure 2.

Predicted 3D structures of the OCA2 protein: (A) Wild type (Met425) and (B) mutant (Arg425) variants, modeled using the Swiss Model server. OCA2, oculocutaneous albinism type 2.

Figure 3.

(A) PPI network analysis for the OCA2 gene, illustrating interactions with genes involved in melanin synthesis and pigmentation processes. (B) Conservation analysis of the methionine residue at position 425 across 13 species, showing complete conservation, which highlights the functional importance of this amino acid in the OCA2 protein. OCA2, oculocutaneous albinism type 2; PPI, protein-protein interaction.

Figure 4.

Sanger sequencing chromatograms confirm the presence of a novel homozygous variant (c.1274T>G; p.Met425Arg) in the OCA2 gene in the proband. Both parents are heterozygous carriers, consistent with autosomal recessive inheritance.