Molecular basis of mouse Himalayan mutation

Kwon, Byoung S.; Halaban, Ruth; Chintamaneni, C

doi:10.1016/0006-291x(89)91588-x

Cited by 67 publications

(45 citation statements)

References 24 publications

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“…These types of observations, first made by Sewall Wright (1917c) and later by Clarence Cook Little (1957) and A. G. Searle (1968), foreshadowed the field of comparative genomics. Indeed, comparison of genome sequences not only clarified the evolutionary relationships among mammals (and most other organisms), but also provided the tools to identify molecular alterations responsible for the Tyrosinase color series in mice (Kwon et al 1989), cats (Lyons et al 2005;Schmidt-Kuntzel et al 2005), cattle (Schmutz et al 2004), and rabbits (Aigner et al 2000) (although, ironically, not yet in guinea pigs).…”

Section: Discussionmentioning

confidence: 99%

Linkage and Segregation Analysis of Black and Brindle Coat Color in Domestic Dogs

et al. 2007

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Mutations of pigment type switching have provided basic insight into melanocortin physiology and evolutionary adaptation. In all vertebrates that have been studied to date, two key genes, Agouti and Melanocortin 1 receptor (Mc1r), encode a ligand-receptor system that controls the switch between synthesis of red-yellow pheomelanin vs. black-brown eumelanin. However, in domestic dogs, historical studies based on pedigree and segregation analysis have suggested that the pigment type-switching system is more complicated and fundamentally different from other mammals. Using a genomewide linkage scan on a Labrador 3 greyhound cross segregating for black, yellow, and brindle coat colors, we demonstrate that pigment type switching is controlled by an additional gene, the K locus. Our results reveal three alleles with a dominance order of black (K B ) . brindle (k br ) . yellow (k y ), whose genetic map position on dog chromosome 16 is distinct from the predicted location of other pigmentation genes. Interaction studies reveal that Mc1r is epistatic to variation at Agouti or K and that the epistatic relationship between Agouti and K depends on the alleles being tested. These findings suggest a molecular model for a new component of the melanocortin signaling pathway and reveal how coat-color patterns and pigmentary diversity have been shaped by recent selection.

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Section: Discussionmentioning

confidence: 99%

Linkage and Segregation Analysis of Black and Brindle Coat Color in Domestic Dogs

et al. 2007

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“…Consequently, melanin synthesis only occurs in cooler areas of the body, such as the arms and legs. The resultant pattern of peripheral pigmentation is analogous to that of the Siamese cat and the Himalayan mouse (7,8). A number of ts variants of tyrosinase have been molecularly cloned.…”

mentioning

confidence: 94%

A Common Temperature-sensitive Allelic Form of Human Tyrosinase Is Retained in the Endoplasmic Reticulum at the Nonpermissive Temperature

Berson¹,

Frank²,

Calvo³

et al. 2000

Journal of Biological Chemistry

116

101

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Oculocutaneous albinism type 1TS is caused by mutations that render the melanocyte-specific enzyme tyrosinase temperature-sensitive (ts); the enzyme is inactive in cells grown at 37°C but displays full activity in cells grown at 31°C. To distinguish whether the ts phenotype of the common R402Q variant of human tyrosinase is due to altered enzymatic activity or to misfolding and a defect in intracellular trafficking, we analyzed its localization and processing in transiently transfected HeLa cells. R402Q tyrosinase accumulates in the endoplasmic reticulum (ER) at 37°C but exits the ER and accumulates in endosomal structures in cells grown at 31°C. The inability of the R402Q variant to exit the ER is confirmed by the failure to acquire endoglycosidase H resistance at 37°C and cannot be accounted for solely by enhanced proteasome-mediated degradation. ER retention at 37°C is mediated by the lumenal domain of R402Q tyrosinase, is not dependent on tethering to the membrane, and is irreversible. Finally, a wild-type allelic form of tyrosinase is partially ts in transiently transfected HeLa cells. The data show that human tyrosinase expressed in non-melanogenic cells folds and exits the ER inefficiently and that R402Q tyrosinase exaggerates this defect, resulting in a failure to exit the ER at physiologic temperatures.

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“…35,36). The Tyr c-h/c-h mouse (also known as the Himalayan mouse), a model of OCA-1B, is homozygous for a Tyr allele that has maximum enzymatic activity below normal body temperature (37°C) because the mutant protein (c.A1259G, p.H420R) is heat labile (37,38). In homozygotes, the first coat was a uniform light tan.…”

Section: Resultsmentioning

confidence: 99%

Nitisinone improves eye and skin pigmentation defects in a mouse model of oculocutaneous albinism

Onojafe¹,

Adams²,

Simeonov³

et al. 2011

J. Clin. Invest.

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Mutation of the tyrosinase gene (TYR) causes oculocutaneous albinism, type 1 (OCA1), a condition characterized by reduced skin and eye melanin pigmentation and by vision loss. The retinal pigment epithelium influences postnatal visual development. Therefore, increasing ocular pigmentation in patients with OCA1 might enhance visual function. There are 2 forms of OCA1, OCA-1A and OCA-1B. Individuals with the former lack functional tyrosinase and therefore lack melanin, while individuals with the latter produce some melanin. We hypothesized that increasing plasma tyrosine concentrations using nitisinone, an FDA-approved inhibitor of tyrosine degradation, could stabilize tyrosinase and improve pigmentation in individuals with OCA1. Here, we tested this hypothesis in mice homozygous for either the Tyr c-2J null allele or the Tyr c-h allele, which model OCA-1A and OCA-1B, respectively. Only nitisinone-treated Tyr c-h/c-h mice manifested increased pigmentation in their fur and irides and had more pigmented melanosomes. High levels of tyrosine improved the stability and enzymatic function of the Tyr c-h protein and also increased overall melanin levels in melanocytes from a human with OCA-1B. These results suggest that the use of nitisinone in OCA-1B patients could improve their pigmentation and potentially ameliorate vision loss.

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Molecular basis of mouse Himalayan mutation

Cited by 67 publications

References 24 publications

Linkage and Segregation Analysis of Black and Brindle Coat Color in Domestic Dogs

Linkage and Segregation Analysis of Black and Brindle Coat Color in Domestic Dogs

A Common Temperature-sensitive Allelic Form of Human Tyrosinase Is Retained in the Endoplasmic Reticulum at the Nonpermissive Temperature

Nitisinone improves eye and skin pigmentation defects in a mouse model of oculocutaneous albinism

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