Molecular basis of type I (tryrosinase-related) oculocutaneous albinism: Mutations and polymorphisms of the human tyrosinase gene

1993 ◽  
Vol 2 (1) ◽  
pp. 1-6 ◽  
Author(s):  
William S. Oetting ◽  
Richard A. King
Keyword(s):  
Molecular Basis ◽  
Oculocutaneous Albinism ◽  
Type I ◽  
Tyrosinase Gene ◽  
Human Tyrosinase

Polymorphic markers of the human tyrosinase gene for indirect gene diagnosis of tyrosinase-related oculocutaneous albinism (OCA1)

1998 ◽  
Vol 16 ◽  
pp. S149
Author(s):  
Jun Matsunaga ◽  
Muneo Tanita ◽  
Miwako Dakeishi-Hara ◽  
Eriko Nakamura ◽  
Yoshinori Miyamura ◽  
...  
Keyword(s):  
Oculocutaneous Albinism ◽  
Polymorphic Markers ◽  
Gene Diagnosis ◽  
Tyrosinase Gene ◽  
Human Tyrosinase

scholarly journals Type I Oculocutaneous Albinism Associated with a Full-Length Deletion of the Tyrosinase Gene

1996 ◽  
Vol 106 (5) ◽  
pp. 1137-1140 ◽  
Author(s):  
Rhonda E. Schnur ◽  
Beatrice T. Sellinger ◽  
Stuart A. Holmes ◽  
Penelope A. Wick ◽  
Yvonne O. Tatsumura ◽  
...  
Keyword(s):  
Oculocutaneous Albinism ◽  
Full Length ◽  
Type I ◽  
Tyrosinase Gene

Tyrosinase gene mutations in type I (tyrosinase-deficient) oculocutaneous albinism define two clusters of missense substitutions

1992 ◽  
Vol 43 (5) ◽  
pp. 865-871 ◽  
Author(s):  
Ram K. Tripathi ◽  
Kathleen M. Strunk ◽  
Lutz B. Giebel ◽  
Richard G. Weleber ◽  
Richard A. Spritz
Keyword(s):  
Gene Mutations ◽  
Oculocutaneous Albinism ◽  
Type I ◽  
Tyrosinase Gene

scholarly journals Five Novel Mutations in Tyrosinase Gene of Japanese and Indian Patients with Oculocutaneous Albinism Type I (OCA1)

2005 ◽  
Vol 125 (2) ◽  
pp. 397-398 ◽  
Author(s):  
Yoshinori Miyamura ◽  
Ishwar C. Verma ◽  
Renu Saxena ◽  
Michiko Hoshi ◽  
Ayumi Murase ◽  
...  
Keyword(s):  
Oculocutaneous Albinism ◽  
Type I ◽  
Novel Mutations ◽  
Tyrosinase Gene ◽  
Indian Patients

scholarly journals Functional in silico analysis of human tyrosinase and OCA1 associated mutations

2020 ◽  
Vol 9 (3) ◽  
pp. 81-92
Author(s):  
Yuri Sergeev ◽  
Milan Patel
Keyword(s):  
Active Site ◽  
In Silico ◽  
In Silico Analysis ◽  
Autosomal Recessive Disorder ◽  
Oculocutaneous Albinism ◽  
General Mechanism ◽  
Site Mutation ◽  
Tyrosinase Gene ◽  
Severity Of The Disease ◽  
Human Tyrosinase

Oculocutaneous albinism type 1 (OCA1) is an autosomal recessive disorder caused by mutations in the tyrosinase gene. OCA1 exists in two forms: OCA1A and OCA1B. OCA1A is caused by a full loss of the human tyrosinase protein (Tyr), leading to an absence of pigment in skin, hair, and eyes, while OCA1B has reduced Tyr catalytic activity and pigment. The current understanding of the disease is hampered by the absence of information regarding the alterations of protein structure and the effects leading to either form of OCA1. Here, we used computational methods to find a general mechanism for establishing this link. Tyr and mutant variants were built through homology modeling, glycosylated in silico, minimized, and simulated using 100 ns molecular dynamics in water. For OCA1B mutants, cavity size is linked to DDG values for mutants, suggesting that partial loss of Tyr is associated with the destabilizing effect of the EGF-like domain movement. In OCA1A, active site mutation simulations indicate that the absence of O2 leads to protein instability. OCA1B mutants are described in severity by the size of the cavity within the EGF–Tyr interface, while active site OCA1A mutants are unable to fully coordinate copper, leading to an absence of O2 and Tyr instability. In patients with known genotypes, free energy changes may help identify the severity of the disease by assessing either the allosteric effect of the EGF-Tyr cavity in OCA1B or the active site instability in OCA1A.

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

2001 ◽  
Vol 355 (2) ◽  
pp. 259-269 ◽  
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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