Assignment of the human TYRP (brown) locus to chromosome region 9p23 by nonradioactive in situ hybridization

doi:10.1016/0888-7543(92)90228-K

Genomics

Volume 13, Issue 1, May 1992, Pages 227-229

https://doi.org/10.1016/0888-7543(92)90228-K Get rights and content

Abstract

The TYRP (brown) locus determines pigmentation and coat color in the mouse. The human homolog of the TYRP locus has been recently identified and shown to encode a 75-kDa transmembrane melanosomal glycoprotein called gp75. The gp75 glycoprotein is homologous to tyrosinase, an enzyme involved in the synthesis of melanin, forming a family of tyrosinase-related proteins. A genomic clone of human gp75 was used to map the human TYRP locus to chromosome 9, region 9p23, by nonradioactive fluorescent in situ hybridization. Specificity of hybridization was tested with a genomic fragment of human tyrosinase that mapped to a distinct site on 11q21. The 9p region has been reported to be nonrandomly altered in human melanoma, suggesting a role for the region near the TYRP locus in melanocyte transformation.

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Cited by (42)

Molecular Biology of Albinism
2018, Albinism in Africa: Historical, Geographic, Medical, Genetic, and Psychosocial Aspects
Specialized pigment cells, including melanocytes and retinal pigment epithelium, synthesize melanin. Skin, hair, and eye pigmentation is a tightly controlled process that requires expression of multiple genes that ensure migration of melanocyte precursors, cell differentiation, regulation of pigmentation, production of melanin and in the case of skin, delivery to keratinocytes where it protects against ultraviolet light. In addition, toxic intermediates produced during melanogenesis require that the process is limited to membrane bound organelles known as melanosomes. A cohort of proteins facilitates melanosome formation, delivery of regulatory proteins and proteins involved in melanin synthesis, as well as translocation of melanosomes to the keratinocyte. The various proteins involved in these processes interact with and modify each other's functions. Albinism results when a gene encoding one of these proteins is mutated. The most common forms of albinism are nonsyndromic oculocutaneous albinism (OCA) types 1–4, which are caused by mutations at the tyrosinase (TYR), OCA2, tyrosinase-related protein 1 (TYRP1) and solute carrier family 45 member 2 (SLC45A2) loci, respectively. Syndromic disorders that include albinism as a feature, such as Hermansky–Pudlak syndrome, result from mutations in genes involved in melanosome biogenesis and transport. This chapter addresses the basic biology of melanocytes and biochemistry of melanin synthesis. The various forms of nonsyndromic and syndromic albinism are described with particular focus on the forms common in Africa.
Abnormalities of Pigmentation
2013, Emery and Rimoin's Principles and Practice of Medical Genetics
Report of a novel OCA2 gene mutation and an investigation of OCA2 variants on melanoma risk in a familial melanoma pedigree
2013, Journal of Dermatological Science
Citation Excerpt :
Oculocutaneous albinism type 2 (OCA2) is caused by mutations in the human OCA2 gene resulting in alterations in the P-protein, thereby disrupting its role in melanin biosynthesis [7]. Oculocutaneous albinism type 3 (OCA3), formerly known as Rufous OCA, is a mild form of albinism seen predominantly in South African blacks and is the result of mutations in the tyrosinase-related protein 1 (TYRP1) gene located at 9p23 [29–31]. The TYRP1 gene codes for the TYRP1 protein, an enzyme which may act downstream of tyrosinase in the eumelanin pathway [32,33].
Oculocutaneous albinism type 2 (OCA2) is caused by mutations of the OCA2 gene. Individuals affected by OCA2 as well as other types of albinism are at a significantly increased risk for sun-induced skin-cancers, including malignant melanoma (MM).
To identify the molecular etiology of oculocutaneous albinism in a previously uncharacterized melanoma pedigree and to investigate the relationship between two OCA2 variants and melanoma predisposition in this pedigree.
DNA and RNA were isolated from the peripheral blood of seven patients in a familial melanoma pedigree. Electron microscopy was performed on the individual with clinical oculocutaneous albinism. OCA2, TYRP1, MC1R, CDKN2A/p16, CDKN2A/p19ARF, and CDK4 genes were sequenced in affected individuals. The relationship between OCA2 variants and melanoma was assessed using a pedigree likelihood-based method.
The proband was determined to be an OCA2 compound heterozygous mutation carrier with a previously reported conservative missense mutation (V443I) and a novel non-conservative missense mutation (L734R). The pedigree contained individuals diagnosed with both cutaneous and iris melanoma. Based on co-segregation analysis, the odds of these OCA2 variants being high penetrance loci for melanoma was: 1.3-to-1 if we include the iris melanoma as affected and 6.5-to-1 if we only consider cutaneous melanoma as affected.
The discovery of this novel OCA2 variant adds to the body of evidence on the detrimental effects of OCA2 gene mutations on pigmentation, supports existing GWAS data on the relevance of the OCA2 gene in melanoma predisposition, and may ultimately assist in the development of targeted molecular therapies in the treatment of OCA and melanoma.
Ocular genetics: Current understanding
2004, Survey of Ophthalmology
Rufous oculocutaneous albinism in Southern African blacks is caused by mutations in the TYRP1 gene
1997, American Journal of Human Genetics
Oculocutaneous albinism (OCA) is the most common autosomal recessive disorder among southern African Blacks. There are three forms that account for almost all OCA types in this region. Tyrosinase-positive OCA (OCA2), which is the most common, affects ∼1/3,900 newborns and has a carrier frequency of ∼1/33. It is caused by mutations in the P gene on chromosome 15. Brown OCA (BOCA) and rufous OCA (ROCA) account for the majority of the remaining phenotypes. The prevalence of BOCA is unknown, but for ROCA it is ∼1/8,500. Linkage analysis performed on nine ROCA families showed that ROCA was linked to an intragenic marker at the TYRP1 locus (maximum LOD score = 3.80 at θ=.00). Mutation analysis of 19 unrelated ROCA individuals revealed a nonsense mutation at codon 166 (S166X) in 17 (45%) of 38 ROCA chromosomes, and a second mutation (368delA) was found in an additional 19 (50%) of 38 chromosomes; mutations were not identified in the remaining 2 ROCA chromosomes. In one family, two siblings with a phenotypically unclassified form of albinism were found to be compound heterozygotes for mutations (S166X/368delA) at the TYRP1 locus and were heterozygous for a common 2.7-kb deletion in the P gene. These findings have highlighted the influence of genetic background on phenotype, in which the genotype at one locus can be influenced by the genotype at a second locus, leading to a modified phenotype. ROCA, which in southern African Blacks is caused by mutations in the TYRP1 gene, therefore should be referred to as “OCA3,” since this is the third locus that has been shown to cause an OCA phenotype in humans.
Tyrosinase and related proteins in mammalian pigmentation
1996, FEBS Letters
Tyrosinase is the key enzyme in pigment synthesis, initiating a cascade of reactions which convert the amino acid tyrosine to the melanin biopolymer. Two other tyrosinase-related proteins (TRP) are known, TRP-1 (probably DHICAoxidase) and TRP-2 (DOPAchrome tautomerase). These proteins show about 40% homology, and recent results have indicated that the genes might be derived from a common ancestor. We will discuss recent findings on genomic organization, and on the proteins and their presumed function, which is important for eumelanin synthesis in mouse and man.

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Genomics

Abstract

References (21)

The human homolog of the mouse brown gene maps to the short arm of chromosome 9 and extends the known region of homology with mouse chromosome 4

Genomics

Human tyrosinase gene, mapped to chromosome 11 (q14→q21), defines second region of homology with mouse chromosome 7

Genomics

Chromosome changes in metastatic human melanoma

Cancer Genet. Cytogenet

Possible involvement of the chromosome region 10q24→q26 in early stages of melanocytic neoplasia

Cancer Genet. Cytogenet

Chromosomal evolution in the progression and metastasis of human malignant melanoma: A multiple lesion study

Cancer Genet. Cytogenet

Nucleotide sequence of the cDNA encoding human tyrosinase-related protein

Nucleic Acids Res

Cytogenetic analysis of melanocytes from premalignant nevi and melanomas

J. Natl. Cancer Inst

Loss of heterozygosity at autosomal and X-linked loci during tumor progression in a patient with melanoma

Cancer Res

Mapping small DNA sequences by fluorescence in situ hybridization directly on banded metaphase chromosomes

A cDNA encoding tyrosinase-related protein maps to the brown locus in mice

Cited by (42)

Molecular Biology of Albinism

Abnormalities of Pigmentation

Report of a novel OCA2 gene mutation and an investigation of OCA2 variants on melanoma risk in a familial melanoma pedigree

Ocular genetics: Current understanding

Rufous oculocutaneous albinism in Southern African blacks is caused by mutations in the TYRP1 gene

Tyrosinase and related proteins in mammalian pigmentation

Short communicationAssignment of the human TYRP (brown) locus to chromosome region 9p23 by nonradioactive in situ hybridization

Abstract

Genomics

Genomics

Cancer Genet. Cytogenet

Cancer Genet. Cytogenet

Cancer Genet. Cytogenet

Nucleotide sequence of the cDNA encoding human tyrosinase-related protein

Nucleic Acids Res

Cytogenetic analysis of melanocytes from premalignant nevi and melanomas

J. Natl. Cancer Inst

Loss of heterozygosity at autosomal and X-linked loci during tumor progression in a patient with melanoma

Cancer Res

Mapping small DNA sequences by fluorescence in situ hybridization directly on banded metaphase chromosomes

A cDNA encoding tyrosinase-related protein maps to the brown locus in mice

Short communication
Assignment of the human TYRP (brown) locus to chromosome region 9p23 by nonradioactive in situ hybridization