title: Germline melanocortin-1-receptor genotype is associated with severity of cutaneous phenotype in congenital melanocytic nevi: a role for MC1R in human fetal development.
abstract: 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.
authors.affiliation: Department of Paediatric Dermatology, Great Ormond Street Hospital for Children, London, UK.
authors.forename: Veronica A
authors.initials: VA
authors.lastname: Kinsler
authors.forename: Sayeda
authors.initials: S
authors.lastname: Abu-Amero
authors.forename: Peter
authors.initials: P
authors.lastname: Budd
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Jackson
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ring
authors.forename: Kate
authors.initials: K
authors.lastname: Northstone
authors.forename: David J
authors.initials: DJ
authors.lastname: Atherton
authors.forename: Neil W
authors.initials: NW
authors.lastname: Bulstrode
authors.forename: Philip
authors.initials: P
authors.lastname: Stanier
authors.forename: Raoul C
authors.initials: RC
authors.lastname: Hennekam
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Sebire
authors.forename: Gudrun E
authors.initials: GE
authors.lastname: Moore
authors.forename: Eugene
authors.initials: E
authors.lastname: Healy
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001724:Birth Weight; D002648:Child; D002675:Child, Preschool; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D018095:Germ-Line Mutation; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009508:Nevus, Pigmented / Q000378:metabolism; D010641:Phenotype; D015995:Prevalence; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*
chemical_list: D044102:Receptor, Melanocortin, Type 1