Germline Melanocortin-1-Receptor Genotype Is Associated with Severity of Cutaneous Phenotype in Congenital Melanocytic Nevi: A Role for MC1R in Human Fetal Development

• Published in: Journal of investigative dermatology Vol. 132; no. 8; pp. 2026 - 2032
• Main Authors: Kinsler, Veronica A., Abu-Amero, Sayeda, Budd, Peter, Jackson, Ian J., Ring, Susan M., Northstone, Kate, Atherton, David J., Bulstrode, Neil W., Stanier, Philip, Hennekam, Raoul C., Sebire, Neil J., Moore, Gudrun E., Healy, Eugene
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2012; Elsevier Limited; Nature Publishing Group
• Subjects: Adolescent; Adult; Alleles; Birth Weight; Child; Child, Preschool; Female; Gene Expression Regulation, Developmental; Genotype; Germ-Line Mutation; Heterozygote; Homozygote; Humans; Infant; Infant, Newborn; Male; Nevus, Pigmented - metabolism; Original; Phenotype; Prevalence; Receptor, Melanocortin, Type 1 - genetics
• ISSN: 0022-202X; 1523-1747; 1523-1747
• DOI: 10.1038/jid.2012.95

Congenital melanocytic nevi (CMN) are pigmented birthmarks that affect up to 80% of the skin surface area. The increased frequency of CMN in families of severely affected individuals is suggestive of a predisposing germline genotype. We noted a high prevalence of red hair in affected families, and considered a role for MC1R in this condition. A cohort of 166 CMN subjects underwent pigmentary phenotyping, with MC1R genotyping in 113. Results were compared with a local control group of 60 unrelated children and with 300 UK children without CMN. CMN subjects had higher prevalences of red hair and a red-haired parent than local controls and had a higher rate of compound heterozygosity and homozygosity for MC1R variants. The presence of a V92M or R allele (D84E, R151C, R160W, D294H) was associated with increasing size of the CMN, implying a growth-promoting effect of these alleles. Unexpectedly, the V92M and R151C alleles were also strongly associated with birth weight in the CMN cohort, a finding confirmed in the control group. The effect of germline MC1R genotype on development and severity of CMN led us to investigate potential broader effects on growth, revealing a role for MC1R in normal fetal development.