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
12851335
TITLE
Genetic association and cellular function of MC1R variant alleles in human pigmentation.
ABSTRACT
We have examined MC1R variant allele frequencies in the general population of South East Queensland and in a collection of adolescent dizygotic and monozygotic twins and family members to define statistical associations with hair and skin color, freckling, and mole count. Results of these studies are consistent with a linear recessive allelic model with multiplicative penetrance in the inheritance of red hair. Four alleles, D84E, R151C, R160W, and D294H, are strongly associated with red hair and fair skin with multinomial regression analysis showing odds ratios of 63, 118, 50, and 94, respectively. An additional three low-penetrance alleles V60L, V92M, and R163Q have odds ratios 6, 5, and 2 relative to the wild-type allele. To address the cellular effects of MC1R variant alleles in signal transduction, we expressed these receptors in permanently transfected HEK293 cells. Measurement of receptor activity via induction of a cAMP-responsive luciferase reporter gene found that the R151C and R160W receptors were active in the presence of NDP-MSH ligand, but at much reduced levels compared with that seen with the wild-type receptor. The ability to stimulate phosphorylation of the cAMP response element binding protein (CREB) transcription factor was also apparent in all stimulated MC1R variant allele-expressing HEK293 cell extracts as assessed by immunoblotting. In contrast, human melanoma cell lines showed wide variation in the their ability to undergo cAMP-mediated CREB phosphorylation. Culture of human melanocytes of known MC1R genotype may provide the best experimental approach to examine the functional consequences for each MC1R variant allele. With this objective, we have established more than 300 melanocyte cell strains of defined MC1R genotype.
DATE PUBLISHED
2003 Jun
HISTORY
PUBSTATUS PUBSTATUSDATE
pubmed 2003/07/10 05:00
medline 2003/08/30 05:00
entrez 2003/07/10 05:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Sturm RA Sturm R A RA Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia. r.sturm@imb.uq.edu.au
Duffy DL Duffy D L DL
Box NF Box N F NF
Newton RA Newton R A RA
Shepherd AG Shepherd A G AG
Chen W Chen W W
Marks LH Marks L H LH
Leonard JH Leonard J H JH
Martin NG Martin N G NG
INVESTIGATORS
JOURNAL
VOLUME: 994
ISSUE:
TITLE: Annals of the New York Academy of Sciences
ISOABBREVIATION: Ann. N. Y. Acad. Sci.
YEAR: 2003
MONTH: Jun
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Print
ISSN: 0077-8923
ISSNTYPE: Print
MEDLINE JOURNAL
MEDLINETA: Ann N Y Acad Sci
COUNTRY: United States
ISSNLINKING: 0077-8923
NLMUNIQUEID: 7506858
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
COMMENTS AND CORRECTIONS
GRANTS
GRANTID AGENCY COUNTRY
CA88363 NCI NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Alleles
Cell Line
Cyclic AMP Response Element-Binding Protein metabolism
Genetic Variation metabolism
Genotype metabolism
Humans metabolism
Melanocytes metabolism
Phenotype metabolism
Pigmentation physiology
Receptors, Corticotropin metabolism
Receptors, Melanocortin metabolism
alpha-MSH metabolism
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Cyclic AMP Response Element-Binding Protein
0 Receptors, Corticotropin
0 Receptors, Melanocortin
581-05-5 alpha-MSH
OTHER ID's