Journal
HUMAN MUTATION
Volume 30, Issue 5, Pages 811-822Publisher
WILEY
DOI: 10.1002/humu.20971
Keywords
melanocortin 1 receptor; MC1R; melanoma; variants; loss of function
Categories
Funding
- Comision Interministerial de Ciencia y Tecnolgia (CICYT), Spain [SAF2006-11206]
- FEDER
- Ministerio de Educacion y Ciencia (MEC) [SAF2007-65542-C02-01]
- Fundacion Mutua Madrilena, Spain
- Ministerio de Sanidad y Consumo [FI05/00918]
- Fundacion paral la Formacion e Investigacion Sanitaria de la Region de Murcia [003/RRIC/07]
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The melanocortin 1 receptor, a Gs protein-coupled receptor expressed in epidermal melanocytes, is a mal determinant of skin pigmentation and phototype and an important contributor to melanoma risk. MC1R activation stimulates synthesis of black, strongly photo-protective cumelanin pigments. Several MC1R alleles are associated with red hair, fair skin, increased sensitivity to ultraviolet radiation, and increased skin cancer risk. The MC1R gene is highly polymorphic, but only, a few naturally occurring alleles have been functionally characterized, which complicates the establishment of accurate correlations between the signaling properties of mutant alleles and defined Cutaneous phenotypes. We report the functional characterization of six MC1R alleles found in Spanish melanoma patients. Two variants (c.152T > C, p.Val51Ala and c.865T > C, p.Cys289Arg) have never been described, and the others (c.112G > A, p.Val38Met; c.122C > T, p.Ser41Phe; c.383T > C, p.Met128Thr; and c.842A > G, p.Asn281Ser) have not been analyzed for function. p.Asn281Ser corresponds to a functionally silent polymorphism. The other mutations are associated with varying degrees of loss of function (LOF), from moderate decreases in coupling to the cAMP pathway (p.Val38Met and p.Val51Ala) to nearly complete absence of functional Coupling (p.Ser41Phe, p.Met128Thr, and p.Cys289Arg). The LOF p.Met128Thr and p.Cys289Arg mutants are trafficked to the cell surface, but are unable to bind agonists efficiently. Conversely, LOF of p.Val38Met, p.Ser41Phe, and p.Val51Ala is due to reduced cell surface expression as a consequence of retention in tire endoplasmic reticulum (ER). Therefore, LOF of MC1R alleles is frequently associated with aberrant forward trafficking and accumulation within the ER or with inability to bind properly the activatory ligand. HUM Mutat 30:811-822, 2009. (C) 2009 Wiley-Liss, Inc.
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