Molecular genetic studies and delineation of the oculocutaneous albinism phenotype in the Pakistani population

<p>Abstract</p> <p>Background</p> <p>Oculocutaneous albinism (OCA) is caused by a group of genetically heterogeneous inherited defects that result in the loss of pigmentation in the eyes, skin and hair. Mutations in the <it>TYR</it>, <it>OCA2</it>, <it>TYRP1</it> and <it>SLC45A2</it> genes have been shown to cause isolated OCA. No comprehensive analysis has been conducted to study the spectrum of <it>OCA</it> alleles prevailing in Pakistani albino populations.</p> <p>Methods</p> <p>We enrolled 40 large Pakistani families and screened them for <it>OCA</it> genes and a candidate gene, <it>SLC24A5</it>. Protein function effects were evaluated using <it>in silico</it> prediction algorithms and <it>ex vivo</it> studies in human melanocytes. The effects of splice-site mutations were determined using an exon-trapping assay.</p> <p>Results</p> <p>Screening of the <it>TYR</it> gene revealed four known (p.Arg299His, p.Pro406Leu, p.Gly419Arg, p.Arg278*) and three novel mutations (p.Pro21Leu, p.Cys35Arg, p.Tyr411His) in ten families. <it>Ex vivo</it> studies revealed the retention of an EGFP-tagged mutant (p.Pro21Leu, p.Cys35Arg or p.Tyr411His) tyrosinase in the endoplasmic reticulum (ER) at 37°C, but a significant fraction of p.Cys35Arg and p.Tyr411His left the ER in cells grown at a permissive temperature (31°C). Three novel (p.Asp486Tyr, p.Leu527Arg, c.1045-15 T > G) and two known mutations (p.Pro743Leu, p.Ala787Thr) of <it>OCA2</it> were found in fourteen families. Exon-trapping assays with a construct containing a novel c.1045-15 T > G mutation revealed an error in splicing. No mutation in <it>TYRP1</it>, <it>SLC45A2,</it> and <it>SLC24A5</it> was found in the remaining 16 families. Clinical evaluation of the families segregating either <it>TYR</it> or <it>OCA2</it> mutations showed nystagmus, photophobia, and loss of pigmentation in the skin or hair follicles. Most of the affected individuals had grayish-blue colored eyes.</p> <p>Conclusions</p> <p>Our results show that ten and fourteen families harbored mutations in the <it>TYR</it> and <it>OCA2</it> genes, respectively. Our findings, along with the results of previous studies, indicate that the p.Cys35Arg, p.Arg278* and p.Gly419Arg alleles of <it>TYR</it> and the p.Asp486Tyr and c.1045-15 T > G alleles of <it>OCA2</it> are the most common causes of OCA in Pakistani families. To the best of our knowledge, this study represents the first documentation of <it>OCA2</it> alleles in the Pakistani population. A significant proportion of our cohort did not have mutations in known <it>OCA</it> genes. Overall, our study contributes to the development of genetic testing protocols and genetic counseling for OCA in Pakistani families.</p