Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.10.3.1 (tyrosinase)
 9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the human tyrosinase gene produce tyrosinase-related oculocutaneous albinism (OCA1, MIM #203100). Tyrosinase is a copper containing enzyme and is responsible for catalyzing the rate limiting step in melanin biosynthesis, the hydroxylation of tyrosine to dopaquinone. We report 13 new mutations in the tyrosinase gene associated with OCA1A (without pigment) and OCA1B (with pigment) including 9 missense mutations (H19Q, R521, R77C, G97R, C289R, L312V, P313R, F340L and H404P), two nonsense mutations (W80X and R116X) and two frameshift mutations (53delG and 223 delG). Our previous work has defined clusters of missense mutations that appear to represent functional domains of the enzyme, and three of the missense mutations fall into these clusters including two (F340L and H404P) that flank the copper B bindng site and the missense mutation R52I that is located in the amino terminal end cluster of the protein. 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. Mutational analysis can provide a definitive diagnosis of the type of OCA as well as help structure/function analysis.
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PMID:Mutations of the human tyrosinase gene associated with tyrosinase related oculocutaneous albinism (OCA1). Mutations in brief no. 204. Online. 1067 Oct 66

Oculocutaneous albinism (OCA) is an autosomal recessive disorder in which the biosynthesis of melanin is reduced or absent in skin, hair and eyes. Tyrosinase-related OCA (OCA1) is caused by mutations in the tyrosinase gene. Tyrosinase-negative OCA (OCA1A) is the most severe phenotype in which tyrosinase catalytic activity is completely lost, resulting in no mature melanin pigment. Yellow OCA (OCA1B) varies from very little pigment associated with whitish-blond hair to nearly normal pigment with dark-blond hair and skin. We determined the tyrosinase activity in melanocytes by the electron microscopic dihydroxyphenylalanine (EM-DOPA) reaction test using skin samples and analyzed tyrosinase gene mutations in nine Japanese patients with OCA. In 18 alleles of nine patients, the OCA1A-associated mutations, P310insC, R77Q and R278X, were found in seven, three and one alleles, respectively. Five patients who had these mutations in both alleles showed white hair, blue eyes and white skin and demonstrated no tyrosinase activity by the EM-DOPA reaction test. Three patients who had no tyrosinase gene mutation showed tyrosinase activity and heterogeneous clinical features. One patient in whom only an R77Q OCA1A mutation was found in one allele demonstrated a reduced tyrosinase activity, indicating OCA1B. This patient had white hair at birth, but it had turned blond by the age of 1 year. These results indicate that the EM-DOPA reaction test provides clear information on the status of tyrosinase activity which is essential for the identification of the disease subtype which in turn is important for the prognosis of patients with OCA.
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PMID:Electron microscopic DOPA reaction test for oculocutaneous albinism. 1092 71

Oculocutaneous albinism (OCA) is a common human genetic condition resulting from mutations in at least twelve different genes. OCA1 results from mutations of the tyrosinase gene and presents with the life-long absence of melanin pigment after birth (OCA1A) or with the development of minimal-to-moderate amounts of cutaneous and ocular pigment (OCA1B). Other types of OCA have variable amounts of cutaneous and ocular pigment. We hypothesized that white hair at birth indicates OCA1 and tested this in a sample of 120 probands with OCA and white hair at birth. We found that 102 (85%) of the probands had OCA1 with one or two identifiable tyrosinase gene mutations, with 169 (83%) of the 204 OCA1 tyrosinase gene alleles having identifiable mutations and 35 (17%) having no identifiable change in the coding, splice junction, or proximal promoter regions of the gene. The inability to identify the mutation was more common with OCA1B (24/35, 69%) than with OCA1A (11/35, 31%) alleles. Seven probands with no tyrosinase gene mutations were found to have OCA2 with one or two P gene mutations, and in eleven, no mutations were detected in either gene. We conclude that (1) the presence of white hair at birth is a useful clinical tool suggesting OCA1 in a child or adult with OCA, although OCA2 may also have this presentation; (2) the molecular analysis of the tyrosinase and P genes are necessary for precise diagnosis; and (3) the presence of alleles without identifiable mutations of the tyrosinase gene, particularly in OCA1B, suggests that more complex mutation mechanisms of this gene are common in OCA.
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PMID:Tyrosinase gene mutations in oculocutaneous albinism 1 (OCA1): definition of the phenotype. 1368 Mar 65

Oculocutaneous albinism type 1 (OCA1) results from mutations in the tyrosinase gene, which lead to partial or complete loss of activity of the corresponding enzyme. A large number of mutations have been identified worldwide, providing insight into the pathogenesis of the disorder. We performed ophthalmic and dermatological exams on 30 Lebanese subjects with oculocutaneous albinism, then screened for mutations in the tyrosinase gene in an effort to establish the molecular basis of the disorder in our population and correlate it with phenotypic findings. The five exons of the gene together with the exon-intron boundaries and part of the promoter region were sequenced. Mutations were found in a total of 14 patients (47%) while no mutation was identified in the sequenced regions in 53% of patients. Fourteen different mutations were identified of which eight were novel while six had been previously reported. Mutations were mainly seen in patients with clinical findings, suggestive of OCA1A (64% of patients with OCA1A versus 25% of patients with OCA1B); therefore, the absence of mutations in some of the other patients may indicate the involvement of other genes.
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PMID:Molecular basis of oculocutaneous albinism type 1 in Lebanese patients. 1593 36

Oculocutaneous albinism type 1 (OCA1) is an autosomal recessive disorder caused by mutations in the tyrosinase gene. Two subtypes of OCA1 have been described: severe OCA1A with complete absence of tyrosinase activity and less severe OCA1B with residual tyrosinase activity. Here, we characterize the recombinant human tyrosinase intramelanosomal domain and mutant variants, which mimic genetic changes in both subtypes of OCA1 patients. Proteins were prepared using site-directed mutagenesis, expressed in insect larvae, purified by chromatography, and characterized by enzymatic activities, tryptophan fluorescence, and Gibbs free energy changes. The OCA1A mutants showed very low protein expression and protein yield and are enzymatically inactive. Mutants mimicking OCA1B were biochemically similar to the wild type, but exhibited lower specific activities and protein stabilities. The results are consistent with clinical data, which indicates that OCA1A mutations inactivate tyrosinase and result in severe phenotype, while OCA1B mutations partially inactivate tyrosinase and result in OCA1B albinism.
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PMID:Oculocutaneous albinism type 1: link between mutations, tyrosinase conformational stability, and enzymatic activity. 2777 80

Human tyrosinase (Tyr) is a Type I membrane glycoprotein that is the rate-limiting enzyme for controlling the production of melanin pigment in melanosomes. Currently, ~300 Tyr mutations are known to be involved in the genetic disease oculocutaneous albinism type 1 (OCA1), which exists in two forms, OCA1A and OCA1B. OCA1A is caused by a full loss of Tyr enzymatic activity, resulting in the absence of pigment in the skin, hair, and eyes, while OCA1B has reduced Tyr activity and pigment. Here, we used molecular modeling to try to understand the role of genetic changes at the protein level in inherited disease. The significant part of Tyr intra-melanosomal domain and five OCA1 mutant variants were built by homology modeling, glycosylated in silico, and refined using molecular dynamics in water. The modeling confirmed experimental results that N347 and N371 glycosylation is vital for protein stability. The changes caused by the T373K mutation indicate a significant impact on protein structure, as expected for OCA1A. In addition, evaluation of free energy changes in OCA1B mutants showed a strong association with the changes observed in our unfolding/refolding experiments in vitro. In conclusion, our results could be useful for understanding the role of OCA1 mutant variants in melanin pigment production, in silico searching for inhibitors and activators of tyrosinase activity, and genotype-to- phenotype analysis in OCA1.
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PMID:Dynamic analysis of human tyrosinase intra-melanosomal domain and mutant variants to further understand oculocutaneous albinism type 1. 3086 38