Mutations in TYR and OCA2 associated with oculocutaneous albinism in Pakistani families

Tyrosinase (TYR) gene sequencing and literature review reveals recurrent mutations and multiple population founder gene mutations as causative of oculocutaneous albinism (OCA) in Pakistani families

“…Out of Table 1). The mutations reported in this study have now been described with varying frequencies in Pakistani families, including very rare/unique mutations (Supplementary Table 1): c.346 C>T and c.715 C>T [19] in just 2 families [20], as well as more common mutations: c.832 C>T in 17 families [4,7,[20][21][22] and c.1255 G>A in 16 families [4,7,19,22]. While it is not possible to conclusively determine whether common TYR mutations represent mutation hotspots versus founder gene mutations without more detailed genetic analyses, evidence to support both mechanisms is present in the literature.…”

“…Several of the TYR mutations described in our study are commonly associated with OCA in Pakistan, and likely represent both regional founder as well as recurrent (hotspot) mutations. For example, the c.832 C> T; p.Arg278Ter c.1255 G>A; p. Gly419Arg variants in TYR identified in families 2, 3, 4 and 6, account for 21%, and 19.75% of all families with known TYR variants in Pakistan, respectively [4,7]. While the frequency of the c.832 C>T variant is higher in the Pakistani population, the mutation has also been identified in many other populations worldwide, indicating that it has likely occurred recurrently, although an increased frequency of the variant in some areas may indicate it has also accumulated as a regional founder mutation (Guayanan 12.5%; Jewish 2.6%; Japanese 22.2%; European 2.5%; Mexican 0.83%; Indian 0.83% and 4.34%; Eastern Indian 8.3%; Syrian 0.83%; Chinese 18.75%) [22].…”

“…Peripheral venous blood samples were taken in EDTA containing vacutainer tubes from each participating individual for genomic DNA extraction, as previously described [4]. One affected individual from each family was sequenced for all five coding exons and associated intron-exon junctions in the TYR gene.…”

“…Non-syndromic OCA is further divided into seven subtypes (OCA1-7) on the basis of genetic testing. Oculocutaneous albinism type 1 (OCA1) is the most common OCA variant affecting almost 50% of affected individuals worldwide [4,5]. Clinically, OCA has a broad clinical presentation, with OCA1A being the most severe subtype with absolute lack of melanin biosynthesis throughout life resulting in completely white hair and skin.…”

“…OCA1A (MIM# 203100) is the most severe clinical phenotype characterised by an almost complete absence of the skin, hair and iris pigmentation, and associated with pathogenic or null alleles in TYR. Less severe TYR mutations may manifest as OCA1B (MIM# 606952), which results in a milder, extremely variable phenotype due to decreased but not completely abrogated tyrosinase activity and low-to-moderate levels of melanin pigmentation in affected individuals [4,14].…”