Tyrosinase (Oculocutaneous Albinism I) (TYR, OCA1)

MUTATION

Allele or SNP

219 mutations deposited in HGMD.
SNPs deposited in dbSNP.
Selected allelic examples described in OMIM.

Distribution

The distribution of mutations and polymorphisms is described in detail in Albinism Database. For cross-reference, view the distribution of mutations and polymorphisms in the Retina International Mutation Database of TYR Gene.

54 novel mutations not appeared in the HGMD database:
(1) Chaki, et al (2006) reported 5 novel mutations (D42N, C91S, E219K, Q326X, G372R) in Indian OCA1 patients.

(2) Hutton, et al (2008a) analyzed Caucasian patients with autosomal recessive ocular albinism (AROA). All were compound heterozygotes with one R402Q allele. One novel mutation (c.47delC) was reported.

(3) Hutton, et al (2008b) reported 8 novel mutations, one frameshift (c.124delG) and seven missense substitutions (F84V, I123T, Y149C, Y181C, H202R, P209L, and L288F) in Caucasian OCA1 patients. They excluded the P152S from a pathological mutation. Among the non-Hispanic Caucasian OCA1 patients, the T373K mutation was most frequent (13.7%). T373K is by far the most frequent OCA1A mutant allele, followed by P81L. V275F and IVS2-7T are the most frequent OCA1B mutant alleles.

(4) Wang, et al (2009) reported 4 novel mutations (C24Y, K142M, G315X, W475X) in Chinese OCA1 patients and first reported two known mutations ( c.896G>A and c.230G>A) in Chinese OCA1 patients.

(5) Rooryck, et al (2008) reported 13 novel ones: three splice site mutations (c.1185 -1 G>T, c.1366 +1 G>A, c.1366 +3A>T), three nonsense mutation (S163X, E219X, K465X), three missense mutations (H19R, K33T, W400C), one frameshift (c.820 -1_820GA>TG, one deletion of three nucleotides (c.505_507delCAG), one deletion of the entire gene (11q14.3 deletion), and one deletion of a single exon (Exon 2 deletion).

(6) Gronskov, et al (2009) reported 8 novel mutations (D76E, A206T, Q255X, C276Y, R299C, M332I, V427F, L452V) in Danish OCA or AROA patients.

(7) Wei, et al (2010) reported 15 previously unreported alleles: p.C24R, p.W39C, p.W39R, p.R77G, p.C100F, p.C100W, p.M185V, p.H211R, p.R212T, p.Y235H, p.W236R, p.D249G, c.1146C>G (p.N382K), p.A481E, and p.G506X in Chinese OCA patients. Interestingly, c.575C>A (p.S192Y) has been reported as a single-nucleotide polymorphism (SNP), rs1042602, in several populations. However, the A allele was not found in any of the 100 unaffected subjects from the Chinese Han population. Two alleles, p.R299H and c.929insC, are the most common alleles in Chinese OCA1 patients, accounting for 15.4% and 14.8%, respectively. About 81% alleles were clustered on exons 1 and 2 of TYR gene in this population.

Note that the 3' region (about 68 kb) of TYR, encompassing exons 4 and 5, has 98.55% sequence identity with a pseudogene (TYRL, 11p11.2, OMIM 191270). A PCR strategy to amplify TYR and TYRL separately was developed by Chaki et al. (2005). They found that the previously reported mutational allele c.1217C4T (p.P406L) was identified as an allele from the pseudogene, TYRL.

Effect

The majority of TYR mutations are missense or nonsense mutations. A large number of mutations have been identified in tyrosinase, with many leading to its misfolding, endoplasmic reticulum (ER) retention, and degradation. Many of the missense mutations are clustered in or flank the copper binding sites by affecting copper binding or by disrupting the substrate binding site (Spritz, et al). The G97R missense mutation is the first identified within the epidermal growth factor (EGF)-like sequence and the H19Q missense mutation alters the cleavage site of the signal peptide sequence (Oetting, et al).