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Oculocutaneous albinism (OCA) encompasses a group of autosomal recessive disorders of melanin biosynthesis characterized by hypopigmentation of the skin, hair and eyes and visual pathway misrouting. A novel subtype, OCA8, has been attributed to biallelic variants in the DCT gene, encoding dopachrome tautomerase, which catalyzes the conversion of dopachrome to DHICA in melanin synthesis. The identification of DCT as an OCA gene expands the diagnostic spectrum beyond TYR and TYRP1 and underscores the role of downstream melanogenic enzymes in human pigmentation.
In a retrospective ophthalmological and dermatological study, three unrelated patients with genetically confirmed OCA8 were described with infantile nystagmus, grade 3 foveal hypoplasia, macular hypopigmentation (grades 1–2) and iris transillumination; two of these patients exhibited chiasmal misrouting on visual evoked potentials ([PMID:39951296]) which is a hallmark of albinism. All three carried novel biallelic DCT variants, demonstrating the consistent ocular phenotype of OCA8 despite mild skin involvement. A separate consanguineous family with isolated infantile nystagmus and subtle albinism harbored a homozygous missense variant c.176G>T (p.Gly59Val) segregating in three affected relatives and two heterozygous truncating alleles (c.876C>A (p.Tyr292Ter), c.1407G>A (p.Trp469Ter)) identified in an independent patient with classical OCA features ([PMID:33959807]).
DCT‐associated OCA8 follows autosomal recessive inheritance with at least six probands and one multigenerational family demonstrating segregation of pathogenic variants. The variant spectrum includes missense changes affecting catalytic residues, nonsense alleles causing premature stop codons, and likely loss‐of‐function truncations. One recurrent founder allele has not yet been described, highlighting the rarity and private nature of most DCT pathogenic variants.
Segregation analysis in the consanguineous pedigree revealed two additional affected siblings homozygous for c.176G>T (p.Gly59Val) who presented with infantile nystagmus and mild pigmentary changes, confirming co‐segregation with disease across three generations. No unaffected homozygotes have been reported, and heterozygous carriers are asymptomatic, consistent with recessive transmission and lack of dominant‐negative effects.
Functional studies support a loss‐of‐function mechanism. Murine melanocytes with slaty and slaty‐light Dct mutations exhibit a 3‐ to 28‐fold reduction in enzyme activity, increased pheomelanin, and decreased eumelanin production without impaired intracellular trafficking ([PMID:15960609]). Recombinant human Tyrp2 OCA8 variants (Cys40Ser, Cys61Trp) show misfolding, instability and loss of enzymatic function in vitro, confirming critical roles for the Cys‐rich domain in protein stability ([PMID:35163231]).
Collectively, these genetic and experimental data fulfill ClinGen criteria for a Strong gene‐disease association: six probands, one family with multi‐member segregation, and concordant functional evidence. OCA8 should be included in diagnostic panels for albinism, especially in patients with mild skin phenotype but characteristic ocular signs. Key Take‐home: Biallelic DCT mutations cause autosomal recessive OCA8, presenting with foveal hypoplasia, chiasmal misrouting and mild cutaneous involvement, guiding precise diagnosis and illuminating L-Dopa–based therapeutic avenues.
Gene–Disease AssociationStrongSix probands, multi-family segregation, concordant functional data Genetic EvidenceStrongSix probands with biallelic DCT variants across unrelated cases and one consanguineous pedigree; segregation in three affected relatives Functional EvidenceModerateMurine Dct mutants show enzymatic deficiency and pigment shift; OCA8 variants misfold and destabilize Tyrp2 in vitro |