Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
17616515
TITLE
Receptor function, dominant negative activity and phenotype correlations for MC1R variant alleles.
ABSTRACT
The human melanocortin-1 receptor (MC1R) is a G-protein coupled receptor involved in the regulation of pigmentation. Several MC1R variant alleles are associated with red hair, fair skin and increased skin cancer risk. We have performed a systematic functional analysis of nine common MC1R variants and correlated these results with the strength of the genetic association of each variant allele with pigmentation phenotypes. In vitro expression studies revealed that variant receptors with reduced cell surface expression, including V60L, D84E, R151C, I155T, R160W and R163Q, showed a corresponding impairment in cAMP coupling. The R142H and D294H variants demonstrated normal cell surface expression, but had reduced functional responses, indicating that altered G-protein coupling may be responsible for this loss of function. The V92M variant cAMP activation was equal to or higher than that for wild-type MC1R. In co-expression studies, the D84E, R151C, I155T and R160W variants showed a dominant negative effect on wild-type receptor cell surface expression, which was reflected in a decreased ability to elevate intracellular cAMP levels. The D294H variant also demonstrated a dominant negative effect on wild-type MC1R cAMP signalling, but had no effect on wild-type surface expression. Importantly, comparison of the in vitro receptor characteristics with skin and hair colour data of individuals both homozygous and heterozygous for MC1R variant alleles revealed parallels between variant MC1R cell surface expression, functional ability, dominant negative activity and their effects on human pigmentation. These findings show the first direct correlations between variant MC1R biochemical properties and pigmentation phenotype.
DATE PUBLISHED
2007 Sep 15
HISTORY
PUBSTATUS PUBSTATUSDATE
aheadofprint 2007/07/05
pubmed 2007/07/10 09:00
medline 2008/01/11 09:00
entrez 2007/07/10 09:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Beaumont KA Beaumont Kimberley A KA Institute for Molecular Bioscience, University of Queensland, Bristane, Australia.
Shekar SN Shekar Sri N SN
Shekar SL Shekar Sri L SL
Newton RA Newton Richard A RA
James MR James Michael R MR
Stow JL Stow Jennifer L JL
Duffy DL Duffy David L DL
Sturm RA Sturm Richard A RA
INVESTIGATORS
JOURNAL
VOLUME: 16
ISSUE: 18
TITLE: Human molecular genetics
ISOABBREVIATION: Hum. Mol. Genet.
YEAR: 2007
MONTH: Sep
DAY: 15
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Print
ISSN: 0964-6906
ISSNTYPE: Print
MEDLINE JOURNAL
MEDLINETA: Hum Mol Genet
COUNTRY: England
ISSNLINKING: 0964-6906
NLMUNIQUEID: 9208958
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
ErratumIn Hum Mol Genet. 2007 Dec 1;16(23):2988 Shekar, Sri L [corrected to Shekar, Sri N]
GRANTS
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Alleles
Amino Acid Substitution
Cell Line
Cyclic AMP metabolism
Gene Expression Regulation physiology
Genes, Dominant physiology
Heterozygote physiology
Homozygote physiology
Humans physiology
Phenotype physiology
Pigmentation physiology
Protein Structure, Tertiary genetics
Receptor, Melanocortin, Type 1 metabolism
Risk Factors metabolism
Signal Transduction physiology
Skin Neoplasms metabolism
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Receptor, Melanocortin, Type 1
E0399OZS9N Cyclic AMP
OTHER ID's