Identification and functional characterization of natural human melanocortin 1 receptor mutant alleles in Pakistani population

Pigment Cell Melanoma Res. 2015 Nov;28(6):730-5. doi: 10.1111/pcmr.12400. Epub 2015 Sep 22.


Melanocortin 1 receptor (MC1R), a Gs protein-coupled receptor of the melanocyte's plasma membrane, is a major determinant of skin pigmentation and phototype. Upon activation by α-melanocyte stimulating hormone, MC1R triggers the cAMP cascade to stimulate eumelanogenesis. We used whole-exome sequencing to identify causative alleles in Pakistani families with skin and hair hypopigmentation. Six MC1R mutations segregated with the phenotype in seven families, including a p.Val174del in-frame deletion and a p.Tyr298* nonsense mutation, that were analyzed for function in heterologous HEK293 cells. p.Tyr298* MC1R showed no agonist-induced signaling to the cAMP or ERK pathways, nor detectable agonist binding. Conversely, signaling was comparable for p.Val174del and wild-type in HEK cells overexpressing the proteins, but binding analysis suggested impaired cell surface expression. Flow cytometry and confocal imaging studies revealed reduced plasma membrane expression of p.Val174del and p.Tyr298*. Therefore, p.Tyr298* was a total loss-of-function (LOF) allele, while p.Val174del displayed a partial LOF attribute.

Keywords: cAMP signaling; hypopigmentation; melanocortin 1 receptor; melanocytes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Family
  • Female
  • Humans
  • Hypopigmentation / genetics
  • Male
  • Mutation / genetics*
  • Pakistan
  • Pedigree
  • Phenotype
  • Receptor, Melanocortin, Type 1 / genetics*


  • Receptor, Melanocortin, Type 1