Comprehensive analysis of the molecular bases of OCA in Indians

Background

OCA is a group of autosomal recessive disorders characterized by hypopigmentation and abnormalities related to ocular development. Mutations in genes regulating melanin-biosynthesis cause four classical types of OCA (OCA 1-4). The clinical spectrum of OCA often depends on the pigmentation threshold of a patient, highlighting the importance of ethnic- specific SNPs. We aimed to understand the molecular bases of OCA in India, where it is one of the four major causes of childhood blindness.

Materials and methods

Blood samples were collected from OCA patients and family members, mostly from eastern and southern India. Seven pigmentation related genes were screened for variations. Relevant non-synonymous changes in tyrosinase (TYR) were functionally validated. Eighteen SNPs from three OCA genes were genotyped in 552 normal individuals covering various ethnic groups of India.

Results

Our data suggest that defects in TYR cause albinism in 58% (36/62) of the cases [1] (and unpublished data; see Figure 1). Functional assays with missense mutations proved that none of mutants are enzymatically active and are retained in the endoplasmic reticulum [1]. Screening of the remaining cases (43%) revealed OCA2 to be the second common locus followed by SLC45A2 [2] (Figure 1). Evaluation of SNPs in TYR, OCA2 and SLC45A2 in normal population suggested definitive bias for some of the SNPs towards specific populations.

Figure 1

Relative contribution of OCA-associated genes towards OCA pathogenesis in India.

Conclusions

Our investigation suggests that ~58% of OCA in India belong to OCA1 category. ER retention is the major cause of lack of TYR activity in OCA1 patients. Information on allelic distribution of SNPs is important for cosegregation analysis of candidate genes in affected families.