Molecular basis for the heterogeneity of human tyrosinase.

A frequent tyrosinase gene mutation in classic, tyrosinase-negative (type IA) oculocutaneous albinism.

“…Thus, the codon 81 proline --leucine substitution is not simply a common nonpathologic polymorphism but instead is apparently causative for type IA OCA. The codon 81 proline -3 leucine substitution does not occur at any of the putative signal peptide, transmembrane, copper-binding, or glycosylation sequences within the tyrosinase polypeptide (5)(6)(7)(8), and so the reason for its deleterious effect is not apparent. However, proline-81 is conserved between human (5, 6) and mouse (7,8,15) tyrosinases, suggesting that it may be important for function.…”

“…In our sequence analysis of her tyrosinase genes, we found only a single base difference from that of normal human tyrosinase cDNA (6). This change, within codon 81 (CCT CTT) results in a proline -* leucine substitution at this site (Fig.…”

“…We detected the codon 81 mutant allele in one additional family; the proband with type IA OCA is heterozygous for this allele. Altogether, we detected the codon 81 mutant allele in 4 of the 15 independently ascertained type I OCA probands; of their 30 total OCA tyrosinase alleles, 6 contained the codon 81 mutation, yielding an overall frequency of this allele among these type I OCA probands of0.2.…”

“…Recently, cDNAs encoding human (5,6) and mouse (7, 8) tyrosinase have been cloned, and the 528-amino acid sequence of the 58-kDA tyrosinase polypeptide (9) has been deduced. Here, we report a missense mutation in the tyrosinase gene coding region in several individuals with classic tyrosinase-negative (type IA) OCA.…”

“…As shown in Fig. 3, exon 1, 2, and 5 primers were derived from the published cDNA sequences (6) and thus amplify only the respective exon sequences. Exon 3 and 4 primers were derived both from the exons and also from the sequences of the adjacent introns (L.B.G., K.M.S., and R.A.S., unpublished data) and thus amplified the exons plus portions of the adjacent introns.…”