scholarly journals Temperature-sensitive oculocutaneous albinism type 1

2020 ◽  
Author(s):  
Keyword(s):  
Oculocutaneous Albinism ◽  
Temperature Sensitive

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.

Biochemical characterization of poliovirus type 1 temperature-sensitive mutants

Virology ◽  
1984 ◽  
Vol 139 (2) ◽  
pp. 403-407 ◽  
Author(s):  
Christine Bellocq ◽  
Henri Agut ◽  
Sylvie Van Der Werf ◽  
Marc Girard
Keyword(s):  
Biochemical Characterization ◽  
Temperature Sensitive ◽  
Poliovirus Type ◽  
Temperature Sensitive Mutants

The R402Q mutation of the Tyrosinase Gene: Lack of Association with oculocutaneous albinism type 1 (OCA1).

2004 ◽  
Vol 17 (4) ◽  
pp. 427-427
Author(s):  
R. A. King ◽  
J. Pietsch ◽  
M. J. Brott ◽  
S. Savage ◽  
J. P. Fryer ◽  
...  
Keyword(s):  
Oculocutaneous Albinism ◽  
Tyrosinase Gene

scholarly journals The consequences of deglycosylation of recombinant intra-melanosomal domain of human tyrosinase

2017 ◽  
Vol 399 (1) ◽  
pp. 73-77 ◽  
Author(s):  
Monika B. Dolinska ◽  
Yuri V. Sergeev
Keyword(s):  
Oculocutaneous Albinism ◽  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Multiple Site ◽  
Insect Larvae ◽  
Melanin Biosynthesis ◽  
Human Tyrosinase

AbstractTyrosinase, a melanosomal glycoenzyme, catalyzes initial steps of the melanin biosynthesis. While glycosylation was previously studiedin vivo, we present three recombinant mutant variants of human tyrosinase, which were obtained using multiple site-directed mutagenesis, expressed in insect larvae, purified and characterized biochemically. The mutagenesis demonstrated the reduced protein expression and enzymatic activity due to possible loss of protein stability and protein degradation. However, the complete deglycosylation of asparagine residuesin vitro, including the residue in position 371, interrupts tyrosinase function, which is consistent with a melanin loss in oculocutaneous albinism type 1 (OCA1) patients.

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