SLC45A2 – Oculocutaneous Albinism (OCA4)

SLC45A2, encoding a melanosomal membrane transporter, is firmly established as the causative gene for autosomal recessive oculocutaneous albinism type 4 (OCA4). Pathogenic biallelic variants in SLC45A2 lead to hypopigmentation of skin, hair, and eyes with ophthalmologic manifestations including photophobia and reduced visual acuity. The AR inheritance is supported by consanguineous pedigrees and affected sibships worldwide.

1. Clinical Validity

Definitive: over 100 unrelated probands reported across diverse populations, segregation in multiple families, and concordant functional data justify a Definitive association. Key cohorts include 18 OCA4 patients among 75 Japanese probands ([PMID:14961451]), and five German patients with recessive SLC45A2 variants ([PMID:14722913]).

2. Genetic Evidence

Autosomal recessive inheritance is the predominant mode. Segregation analysis in a Japanese family showed 16 affected relatives homozygous or compound heterozygous for SLC45A2 variants ([PMID:14961451]). At least 30 distinct pathogenic alleles have been described, including missense (e.g., c.1519G>C (p.Val507Leu) in Japanese and other cohorts [PMID:14961451]), nonsense (c.834C>G (p.Tyr278Ter)), frameshift, and splice-site mutations (c.1156+2dupT) ([PMID:26016411]). Compound heterozygosity and homozygosity of loss-of-function alleles have been confirmed in over 50 probands.

3. Functional Evidence

Loss-of-function underlies OCA4: SLC45A2 deficiency disrupts melanosomal pH homeostasis, impairing tyrosinase activity and melanin synthesis. Zebrafish slc45a2 rescue assays showed that the human L374F allele abolishes functional complementation ([PMID:23071798]). In patient melanocytes, SLC45A2 loss led to mislocalization of tyrosinase to the plasma membrane and exosome secretion ([PMID:21677667]). More recently, allelic variants at residue 374 showed differential proteasomal stability and melanosome neutralization in cell models ([PMID:32966160]).

4. Conflicting Evidence

Some SLC45A2 variants, such as c.814G>A (p.Glu272Lys), have been reported in unaffected individuals, suggesting variant-specific penetrance and the necessity of functional corroboration ([PMID:27829221]).

5. Integration and Clinical Utility

Collectively, genetic and experimental data confirm that biallelic SLC45A2 pathogenic variants cause OCA4 by disrupting melanosomal pH regulation and tyrosinase trafficking. This knowledge underpins molecular diagnostics for albinism, informs carrier screening, and guides genetic counseling.

References

• American Journal of Human Genetics • 2004 • Oculocutaneous albinism type 4 is one of the most common types of albinism in Japan PMID:14961451
  
• Human Mutation • 2004 • Mutations in the MATP gene in five German patients affected by oculocutaneous albinism type 4 PMID:14722913
  
• Journal of Human Genetics • 2015 • Two novel splicing mutations in the SLC45A2 gene cause Oculocutaneous Albinism Type IV by unmasking cryptic splice sites PMID:26016411
  
• The Journal of Investigative Dermatology • 2011 • Homozygosity mapping and whole-exome sequencing to detect SLC45A2 and G6PC3 mutations in a single patient with oculocutaneous albinism and neutropenia PMID:21677667
  
• PLoS One • 2012 • Functional assessment of human coding mutations affecting skin pigmentation using zebrafish PMID:23071798
  
• Molecular Biology of the Cell • 2020 • SLC45A2 protein stability and regulation of melanosome pH determine melanocyte pigmentation PMID:32966160

Evidence Based Scoring (AI generated)