Molecular basis of tyrosinase-negative oculocutaneous albinism. A single base mutation in the tyrosinase gene causing arginine to glutamine substitution at position 59.

Background: Non syndromic oculocutaneous albinism type (OCA) is caused by mutations in tyrosinase (TYR), OCA2, TYRP1, MATP (SLC45A2), SLC24A5 and C10ORF11 genes. Screening for mutations is important in families with oculocutaneous albinism patients in order to accurately diagnose the albinism type, genetic counseling and future therapeutic purposes. Objectives: The Aim of this study was to investigate the founder effect of most frequent mutations in OCA patients. Methods: TYR gene was sequenced in 26 unrelated inbred OCA families as well as 56 unrelated healthy individuals. In addition, homozygosity mapping was performed using 13 STR markers for 6 OCA loci (TYR, OCA2, TYRP1, MATP (SLC45A2), SLC24A5 and C10ORF11 genes). Different mutations were found in these genes from which a single base duplication (c.286dupA) and two single base substitutions c.996G > A (p.M332I) and c.230G > A (p.R77Q) had the most frequencies among the OCA families. In order to investigate the founder effect of these mutations, the haplotypes of two STR markers (TYR-S1 and TYR-S2) inside the TYR gene were ascertained. Results: It was revealed that families with similar mutation harbored similar haplotype for the TYR STR markers too. Conclusions: We conclude that these mutations are possible founder mutations in the Iranian population.

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Molecular Bases of Tyrosinase-Negative Oculocutaneous Albinism: A Single Base Insertion or a Missense Point Mutation in the Tyrosinase Gene

Pigment Cell Research ◽

10.1111/j.1600-0749.1990.tb00356.x ◽

2008 ◽

Vol 3 ◽

pp. 96-100

Author(s):

Yasushi Tomita ◽

Atsushi Takeda ◽

Jun Matsunaga ◽

Shoji Okinaga ◽

Shigeki Shibahara ◽

...

Keyword(s):

Point Mutation ◽

Oculocutaneous Albinism ◽

Single Base ◽

Tyrosinase Gene ◽

Molecular Bases ◽

Base Insertion

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A single base insertion in the putative transmembrane domain of the tyrosinase gene as a cause for tyrosinase-negative oculocutaneous albinism.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.88.12.5272 ◽

1991 ◽

Vol 88 (12) ◽

pp. 5272-5276 ◽

Cited By ~ 29

Author(s):

C. D. Chintamaneni ◽

R. Halaban ◽

Y. Kobayashi ◽

C. J. Witkop ◽

B. S. Kwon

Keyword(s):

Transmembrane Domain ◽

Oculocutaneous Albinism ◽

Single Base ◽

Putative Transmembrane Domain ◽

Tyrosinase Gene ◽

Base Insertion

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Comprehensive analysis of the molecular basis of oculocutaneous albinism in Indian patients lacking a mutation in the tyrosinase gene

British Journal of Dermatology ◽

10.1111/j.1365-2133.2010.09830.x ◽

2010 ◽

Vol 163 (3) ◽

pp. 487-494 ◽

Cited By ~ 8

Author(s):

M. Sengupta ◽

M. Mondal ◽

P. Jaiswal ◽

S. Sinha ◽

M. Chaki ◽

...

Keyword(s):

Molecular Basis ◽

Oculocutaneous Albinism ◽

Comprehensive Analysis ◽

Tyrosinase Gene ◽

Indian Patients

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The molecular basis of oculocutaneous albinism type 1 (OCA1): sorting failure and degradation of mutant tyrosinases results in a lack of pigmentation

Biochemical Journal ◽

10.1042/bj3550259 ◽

2001 ◽

Vol 355 (2) ◽

pp. 259-269 ◽

Cited By ~ 49

Author(s):

Kazutomo TOYOFUKU ◽

Ikuo WADA ◽

Richard A. SPRITZ ◽

Vincent J. HEARING

Keyword(s):

Molecular Basis ◽

Control Process ◽

Large Deletion ◽

Oculocutaneous Albinism ◽

Temperature Sensitive ◽

Tyrosinase Gene ◽

Catalytic Function ◽

Quality Control Process ◽

Early Processing

Oculocutaneous albinism type 1 (OCA1) is an autosomal recessive disease resulting from mutations of the tyrosinase gene (TYR). To elucidate the molecular basis of OCA1 phenotypes, we analysed the early processing and maturation of several different types of mutant tyrosinase with various degrees of structural abnormalities (i.e. two large deletion mutants, two missense mutants that completely destroy catalytic function and three missense mutants that have a temperature-sensitive phenotype). When expressed in COS7 cells, all mutant tyrosinases were sensitive to endoglycosidase H digestion, and immunostaining showed their localization in the endoplasmic reticulum (ER) and their failure to be sorted further to their target organelles. Pulse-chase experiments showed that all mutant tyrosinases were retained by calnexin in the ER and that they were degraded at similarly rapid rates, which coincided with their dissociation from calnexin. Temperature-sensitive mutant enzymes were sorted more efficiently at 31°C than at 37°C, and their degradation was accelerated at 37°C compared with 31°C. Thus in contrast to the current concept that mutant tyrosinases are transported to melanosomes but are functionally inactive there, our results suggest that mutant tyrosinases may not be transported to melanosomes in the first place. We conclude that a significant component of mutant tyrosinase malfunction in OCA1 results from their retention and degradation in the ER compartment. This quality-control process is highly sensitive to minimal changes in protein folding, and so even relatively minor mutations in peripheral sequences of the enzyme not involved with catalytic activity may result in a significant reduction of functional enzyme in melanosomes.

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