Inherited disorders of pigmentation

Witkop, Carl J.

doi:10.1016/0738-081x(85)90097-5

Cited by 52 publications

(26 citation statements)

References 333 publications

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“…Many different types of oculocutaneous and ocular albinism have been reported based on clinical and biochemical analysis [Witkop, 1985]. The cloning and mutational analysis of the genes involved in melanin synthesis now provide a better understanding of the molecular basis of these different phenotypes.…”

Section: Clinical Relevancementioning

confidence: 99%

Molecular basis of albinism: Mutations and polymorphisms of pigmentation genes associated with albinism

Oetting¹,

1999

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Section: Clinical Relevancementioning

confidence: 99%

Molecular basis of albinism: Mutations and polymorphisms of pigmentation genes associated with albinism

Oetting¹,

1999

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“…These include OCA1B (affected individuals are born with white skin and hair but develop some pigment with age and express less severe ocular findings than in OCA1A), OCA1TS (tyrosinase is temperature-sensitive and active in cooler regions of the body resulting in a phenotype similar to that of the Siamese cat) and platinum OCA (small amounts of pigment accumulate in the hair and eyes in late childhood resulting in a silver tinge). [22] A recent study identified a potential therapeutic for OCA1 where some tyrosinase activity is present. Onojafe et al, [23] having noted that nitisinone (used in the treatment of hereditary tyrosinemia type 1) caused an increase in serum tyrosine levels, treated OCA1B mice with the drug and noted an improvement in pigmentation of the mice.…”

Section: Oca1mentioning

confidence: 99%

Biology and genetics of oculocutaneous albinism and vitiligo – common pigmentation disorders in southern Africa

et al. 2013

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The primary pigment that determines human skin, hair and eye colour is melanin, which is synthesised by melanocytes. Melanin protects the skin from ultraviolet (UV) radiation and there is an inverse correlation between the degree of constitutive pigmentation and the risk of sun-induced skin cancers. Besides the life-threatening cancer risk, loss of pigmentation results in premature aging, compromised cutaneous immunity and significant emotional distress to affected individuals. [1][2][3] During embryonic development, melanocyte precursors that arise from the neural crest populate several areas including the interfollicular epidermis and hair follicle bulge in the skin; the uveal tract of the eye; and the stria vascularis, vestibular apparatus and endolymphatic sac of the ear. The development of melanocytes is tightly regulated at the genetic level by a number of genes that control proliferation, survival and migration of precursor cells to the various sites of the body and their differentiation into active melanocytes. A key regulator of this process is the microphthalmia transcription factor (MITF), which has been dubbed the 'master regulator' of the melanocyte, capable of modulating expression of several melanocytespecific proteins.[4] MITF mutations result in Waardenburg syndrome type II.[5] Once the melanocyte has differentiated, MITF regulates expression of genes in response to UV exposure, facilitating the tanning response.Melanocytes produce two forms of melanin, black-brown eumelanin and red-yellow pheomelanin. Skin and hair colour Corresponding author: P Manga (prashiela.manga@nyumc.org)Pigmentation disorders span the genetic spectrum from single-gene autosomal recessive disorders such as oculocutaneous albinism (OCA), the autosomal dominant disorder piebaldism to X-linked ocular albinism and multifactorial vitiligo. OCA connotes a group of disorders that result in hypopigmented skin due to decreased melanin production in melanocytes and loss of visual acuity. There are four non-syndromic forms, OCA1-4, which are classified based on the gene that is mutated (tyrosinase, OCA2, tyrosinase-related protein 1 and SLC45A2, respectively). Despite the fact that multiple genes account for the various forms of OCA, the phenotypes of all four forms result from disruption in the maturation and trafficking of the enzyme tyrosinase. OCA2 is the most prevalent autosomal recessive disorder among southern African blacks, affecting 1/3 900 individuals; while OCA3, although rare, is most prevalent in southern Africa. Another common pigmentation disorder in southern Africa is vitiligo, which affects 1 -2% of people worldwide. Vitiligo is a complex, acquired disorder in which melanocytes are destroyed due to an autoimmune response. The aetiology underlying this disorder is poorly understood, although recent genetic association studies have begun to shed light on the contributing factors. Pigmentation disorders have significant psychosocial implications and co-morbidities, yet therapies are still lacking. Recent progress in...

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“…It is a key enzyme in melanin biosynthesis. Oculocutaneous albinism, a group of autosomal-recessive diseases in humans (2) and animals, is characterized by reduced or absent melanin in skin, hair, and eyes. Tyrosinase-negative albino melanocytes have no tyrosinase activity in vitro.…”

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confidence: 99%

Isolation and sequence of a cDNA clone for human tyrosinase that maps at the mouse c-albino locus.

Kwon

Haq

Pomerantz

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

403

217

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Screening of a Xgtll human melanocyte cDNA library with antibodies against hamster tyrosinase (monophenol, L-dopa:oxygen oxidoreductase, EC 1.14.18.1) resulted in the isolation of 16 clones. The cDNA inserts from 13 of the 16 clones cross-hybridized with each other, indicating that they were from related mRNA species. One of the cDNA clones, Pmel34, detected one mRNA species with an approximate length of 2.4 kilobases that was expressed preferentially in normal and malignant melanocytes but not in other cell types. The amino acid sequence deduced from the nucleotide sequence showed that the putative human tyrosinase is composed of 548 amino acids with a molecular weight of 62,610. The deduced protein contains glycosylation sites and histidinerich sites that could be used for copper binding. Southern blot analysis of DNA derived from newborn mice carrying lethal albino deletion mutations revealed that Pmel34 maps near or at the c-albino locus, the position of the structural gene for tyrosinase.Tyrosinase (monophenol, L-dopa:oxygen oxidoreductase, EC 1.14.18.1) is a copper-based oxidoreductase that catalyzes the oxidation of tyrosine to dopa and the oxidation of dopa to dopaquinone (1). It is a key enzyme in melanin biosynthesis. Oculocutaneous albinism, a group of autosomal-recessive diseases in humans (2) and animals, is characterized by reduced or absent melanin in skin, hair, and eyes. Tyrosinase-negative albino melanocytes have no tyrosinase activity in vitro.Genetic control of pigmentation has been extensively studied in mice. There is evidence that the c-albino locus at chromosome 7 codes for the structural gene for tyrosinase (3,4). Mutations at this locus affect both tyrosinase activity and coat color (5, 6).A nucleic acid probe for tyrosinase would be an invaluable tool for studies of the regulation of tyrosinase, of the molecular basis of human albinism, and of various mouse mutations affecting coat and eye color. We report here the isolation and sequence of a cDNA clone for human tyrosinase that maps at or near the mouse c-locus. ¶ MATERIALS AND METHODS Cell Culture. Normal human melanocytes, melanotic melanoma cells (LG), and neuroblastoma cells (SK-N-SH) were cultured as described (7-9). The murine neuroblastoma cell line NIE115 was obtained from X. 0. Breakefield (E. K. Shriver Center, Waltham, MA). Proteins of normal melanocytes were radiolabeled with [355]methionine (Amersham) (100 ,XCi/ml, 1390 Ci/mmol; 1 Ci = 37 GBq) as described (10).cDNA Libraries and Screening. RNA from normal human melanocytes was prepared, and poly(A)+ RNA was purified on an oligo[d(T)I-cellulose column (11,12). A cDNA li was prepared employing a Xgtll cloning vector (13-15) Xgtll library contained 1.7 x 106 independent phages immunobiological screening and analysis of the fusion teins produced by Xgtll cDNA clones were carried c described by Young and Davis (15). The rabbit anti-hal tyrosinase antibodies and their application in the stun tyrosinases have been described in detail (10, 16).RNA Blot Hybridization. ...

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Inherited disorders of pigmentation

Cited by 52 publications

References 333 publications

Molecular basis of albinism: Mutations and polymorphisms of pigmentation genes associated with albinism

Molecular basis of albinism: Mutations and polymorphisms of pigmentation genes associated with albinism

Biology and genetics of oculocutaneous albinism and vitiligo – common pigmentation disorders in southern Africa

Isolation and sequence of a cDNA clone for human tyrosinase that maps at the mouse c-albino locus.

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