Introduction
Oculocutaneous albinism (OCA) is a group of heterogeneous and autosomal recessive disorders characterized by a reduction or complete loss of melanin biosynthesis in melanocytes (1). All types of OCA demonstrate a lack of melanin pigment in the skin, hair and eyes, and are often accompanied by ocular abnormalities, including varying degrees of nystagmus, hypopigmentation of the iris, foveal hypoplasia, poor vision and refractive errors, photophobia and occasionally color vision impairment (2). The prevalence of OCA subtypes varies considerably between ethnicities. OCA has a prevalence of ~1:20,000 individuals worldwide, or ~1:18,000 in the Chinese Han population (3). At least 17 genes, including four non-syndromic and 13 syndromic, have been identified to be associated with OCA. The tyrosinase (TYR), oculocutaneous albinism II, tyrosinase-related protein 1 and solute carrier family 45, member 2 genes are the four non-syndromic OCA genes and are responsible for OCA type 1 (OCA1; MIM 203100), type 2 (OCA2; MIM 203200), type 3 (OCA3; MIM 203290), and type 4 (OCA4; MIM 606574), respectively. The 13 syndromic OCA genes include the Hermansky-Pudlak syndrome 1 (HPS1), adaptor-related protein complex 3, β 1 subunit, HPS3, HPS4, HPS5, HPS6, dystrobrevin binding protein 1, biogenesis of lysosomal organelles complex-1 subunit 3 (BLOC1S3), BLOC1S6, lysosomal trafficking regulator, myosin VA, ras-related protein and melanophilin genes (4,5). Due to the phenotypic variation and overlap in clinical presentation among different OCA subtypes, genetic analysis is essential to identify the gene defect and the subtype of OCA (6).
OCA1 is the most severe and common form of OCA, and is caused by mutations of the TYR gene (7). It is often divided into two categories: OCA1A and OCA1B. Patients with OCA1A are characterized by a lifelong and complete absence of pigment in the skin, hair and eyes. Patients with OCA1B may have a reduced activity of tyrosinase and may produce some melanin over time, resulting in a darkening of hair (3,8). OCA1 affects ~1 in 40,000 individuals in the majority of populations, and has been reported to be the most common subtype of OCA in Japanese, non-Hispanic Caucasian and Danish populations (9). It accounts for ~64.3% of patients with OCA in China. However, OCA1 is rare among African-Americans, reflecting a population-specific distribution of different OCA subtypes (6).
The present study aimed to identify the genetic mutation responsible for OCA1 in a four-generation family of Chinese origin. Patients in the family presented with typical OCA1 characteristics, including white hair and skin, nystagmus, impaired visual acuity, photophobia, color vision impairment, refractive errors, foveal hypoplasia and iris hypopigmentation and translucency. The p.R299H variant of the TYR gene, predicted to disrupt the overall integrity of tyrosinase, was revealed to co-segregate with patients in this family and was absent in healthy controls, indicating that it is a pathogenic mutation.
Discussion
Albinism was one of the earliest genetic disorders to be studied. In 1903, Farabee (13) first suggested that human albinism may be recessively inherited. The mouse and human TYR genes were isolated in 1987. In 1989, the first mutation (nonsense mutation) in the TYR gene responsible for human OCA was reported by Tomita et al (14). There are 349 TYR sequence variants recorded in the Human Gene Mutation Database (www.hgmd.cf.ac.uk/ac/index.php). A wide spectrum of mutations, including gross and small deletions, small insertions, small indels, and splicing, missense and nonsense mutations, have been described, with missense mutations being the most common.
The TYR gene (MIM 606933) is located on chromosome 11q14.3, and contains 5 exons spanning ~65 kb of genomic DNA. It encodes a 529-amino acid protein, tyrosinase. Tyrosinase consists of an 18-amino acid signal peptide, two copper binding sites, a transmembrane region at the C-terminal end and an epidermal growth factor-like motif (15). It is a glycoprotein and a copper-containing oxidase, and is expressed in melanocytes. Tyrosinase serves an important role in melanin biosynthesis by catalyzing the rate-limiting conversions of tyrosine to dihydroxy-phenylalanine (DOPA) and from DOPA to DOPA-quinone. In addition, it may catalyze the conversion of 5,6-dihydroxyindole to indole-5,6 quinone (16). Mutations in the TYR gene lead to decreased or even absent tyrosinase enzyme activity, and subsequently, a decreased or complete loss of melanin synthesis. Numerous missense mutations are located in or adjacent to the copper binding sites, and interrupt the normal function of tyrosinase, by affecting copper binding or by disrupting the substrate binding site (17).
The present study examined a Chinese Han family with OCA1, characterized by white hair that had not altered in color with age, white skin, nystagmus, impaired visual acuity, photophobia, color vision impairment, refractive errors, foveal hypoplasia and iris hypopigmentation and translucency. The homozygous c.896G>A variant (p.R299H, rs61754375) in the TYR gene was identified in the two patients in the family and was absent in the 100 unrelated ethnicity-matched controls. The mutation was predicted to be ‘probably damaging’ by PolyPhen-2, ‘damaging’ by SIFT and ‘disease-causing’ by MutationTaster. These results suggested that the c.896G>A variant (p.R299H) may be pathogenic. Multiple sequence alignment demonstrated that the arginine residue is highly conserved among vertebrates, suggesting that it may be important for function. The parents of the patients, with a heterozygous p.R299H mutation in the TYR gene, presented a typical phenotype with no symptoms of OCA. Notably, homozygous and heterozygous p.R299H mutations in the TYR gene have been frequently identified in Chinese, Caucasian, Korean and Arabian patients with OCA1, indicating that this location is a mutation hotspot in OCA1 (7,17–20).
Albinism is understood to occur in the majority of fish, birds, reptiles, amphibians and mammals (21). Molecular abnormalities in the Tyr gene that are associated with OCA have been described in whales, chickens, mice, rats, cats, rabbits, cattle, buffalo, American mink, ferrets and rhesus monkeys (22). In 2005, Blaszczyk et al (23) identified the mutation p.R299H in the albino Wistar rat, emphasizing the functional significance of this mutation leading to OCA.
In conclusion, the results of the present study confirmed the clinical diagnosis of OCA1 in a Chinese family by identifying a p.R299H mutation in the TYR gene. These findings suggested that exome sequencing may be a cost-effective tool for accurate diagnosis of the disease, therefore providing genetic counseling options for individuals with OCA. Further studies using appropriate TYR-deficient animal models may facilitate the development of novel therapeutic strategies for the treatment of this disease.