Detection of Mutations in the Tyrosinase Gene in a Patient with Type IA Oculocutaneous Albinism

Spritz, Richard A.; Strunk, Kathleen M.; Giebel, Lutz B.; King, Richard A.

doi:10.1056/nejm199006143222407

Cited by 84 publications

(51 citation statements)

References 23 publications

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“…Individuals with OCA1 show a complete absence of pigment in their skin, eyes and hair; this persists throughout life in the subtype OCA1A (Spritz et al, 1990), whereas patients with subtype OCA1B have some residual tyrosinase activity and thus gradually accumulate minor amounts of pigment in their tissues (Oetting and King, 1999). OCA2 is the most common form of albinism; patients are usually born with minimal pigmentation and become darker during adulthood, finally showing minimal-to-moderate pigmentation of their skin, hair and eyes (King, 1998;Manga and Orlow, 1999).…”

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confidence: 99%

Tyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the underwhite (uw) mutation. A model for oculocutaneous albinism (OCA) type 4

Costin

Valencia

Vieira

et al. 2003

Journal of Cell Science

164

123

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Oculocutaneous albinism (OCA) type 4 is a newly identified human autosomal recessive hypopigmentary disorder that disrupts pigmentation in the skin, hair and eyes. Three other forms of OCA have been previously characterized, each resulting from the aberrant processing and/or sorting of tyrosinase, the enzyme critical to pigment production in mammals. The disruption of tyrosinase trafficking occurs at the level of the endoplasmic reticulum (ER) in OCA1 and OCA3, but at the post-Golgi level in OCA2. The gene responsible for OCA4 is the human homologue of the mouse underwhite (uw) gene, which encodes the membrane-associated transporter protein (MATP). To characterize OCA4, we investigated the processing and sorting of melanogenic proteins in primary melanocytes derived from uw/uw mice and from wild-type mice. OCA4 melanocytes were found to be constantly secreted into the medium dark vesicles that contain tyrosinase and two other melanogenic enzymes, Tyrp1(tyrosinase-related protein 1) and Dct (DOPAchrome tautomerase); this secretory process is not seen in wild-type melanocytes. Although tyrosinase was synthesized at comparable rates in wild-type and in uw-mutant melanocytes,tyrosinase activity in uw-mutant melanocytes was only about 20% of that found in wild-type melanocytes, and was enriched only about threefold in melanosomes compared with the ninefold enrichment in wild-type melanocytes. OCA4 melanocytes showed a marked difference from wild-type melanocytes in that tyrosinase was abnormally secreted from the cells, a process similar to that seen in OCA2 melanocytes, which results from a mutation of the pink-eyed dilution (P) gene. The P protein and MATP have 12 transmembrane regions and are predicted to function as transporters. Ultrastructural analysis shows that the vesicles secreted from OCA4 melanocytes are mostly early stage melanosomes. Taken together, our results show that in OCA4 melanocytes, tyrosinase processing and intracellular trafficking to the melanosome is disrupted and the enzyme is abnormally secreted from the cells in immature melanosomes, which disrupts the normal maturation process of those organelles. This mechanism explains the hypopigmentary phenotype of these cells and provides new insights into the involvement of transporters in the normal physiology of melanocytes.

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confidence: 99%

Tyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the underwhite (uw) mutation. A model for oculocutaneous albinism (OCA) type 4

Costin

Valencia

Vieira

et al. 2003

Journal of Cell Science

164

123

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“…The c-locus in the mouse appears to represent the tyrosinase gene, and a series ofc-locus alleles have been described that correlate with characteristic hypopigmented phenotypes, including the chinchilla, platinum, and Himalayan. A similar series of tyrosinase alleles appears to be present in human, including type IA, IB, and possibly minimal pigment OCA (16,19). The phenotype described in this report apparently results from a novel allele that encodes a temperature-sensitive form of tyrosinase.…”

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confidence: 99%

“…There are more than 60 loci in the mouse that control coat color, but mutations at only one or two produce OCA (16). The c-locus in the mouse appears to represent the tyrosinase gene, and a series ofc-locus alleles have been described that correlate with characteristic hypopigmented phenotypes, including the chinchilla, platinum, and Himalayan.…”

Section: Discussionmentioning

confidence: 99%

“…The tyrosinase gene of the Himalayan mouse has now been cloned and has been shown to contain an A -* G substitution in codon 402 that results in a his -arg amino acid substitution in the peptide (22). The mutation does not occur in an area that is thought to be a potential glycosylation site (16), and site-directed mutagenesis and expression studies will be necessary to determine the precise mechanism for the change in thermostability with this mutation.…”

Section: Discussionmentioning

confidence: 99%

“…At least three types are related to abnormalities of tyrosinase, the enzyme catalyzing the initial two steps in the melanin biosynthetic pathway: the hydroxylation of tyrosine to dopa and the dehydrogenation of dopa to dopaquinone (15). Type IA (tyrosinase negative) OCA is characterized by the total, life-long absence of melanin synthesis associated with a lack of demonstrable tyrosinase activity in all tissues of an affected individual (1,14,16). In type IB (yellow) OCA the phenotype is similar to type IA at birth, but pheomelanin develops in the hair within the first few years of life, followed by eumelanin in the adult (2), suggesting that some residual tyrosinase activity remains in the melanocytes.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Temperature-sensitive tyrosinase associated with peripheral pigmentation in oculocutaneous albinism.

King

Townsend

Oetting³

et al. 1991

J. Clin. Invest.

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Several types of autosomal recessive oculocutaneous albinism (OCA) are associated with abnormal tyrosinase function and a generalized reduction in or absence of cutaneous and eye melanin. Each is thought to result from a different mutant allele at the tyrosinase locus, with the mutation producing an enzyme with little or no activity in all involved tissues. In this paper, we report a new type of OCA that results from a tyrosinase allele producing a temperature-sensitive enzyme. The proband had white hair in the warmer areas (scalp and axilla) and progressively darker hair in the cooler areas (extremities) of her body. Melanocyte and melanosome architecture were normal. Quantitative hairbulb tyrosinase (dopa oxidase) assay demonstrated a loss of activity above 35-37°C. Plasma pheomelanin and urine eumelanin intermediates were reduced and correlated with hair melanin content. This is the first temperature-sensitive tyrosinase mutation to be reported in humans and is analogous to the Siamese mutation in the cat and the Himalayan mutation in the mouse. (J. Clin.

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The Molecular Genetics of Albinism and Piebaldism

Tomita¹

1994

Arch Dermatol

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Detection of Mutations in the Tyrosinase Gene in a Patient with Type IA Oculocutaneous Albinism

Cited by 84 publications

References 23 publications

Tyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the underwhite (uw) mutation. A model for oculocutaneous albinism (OCA) type 4

Tyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the underwhite (uw) mutation. A model for oculocutaneous albinism (OCA) type 4

Temperature-sensitive tyrosinase associated with peripheral pigmentation in oculocutaneous albinism.

The Molecular Genetics of Albinism and Piebaldism

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