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

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

Author information

1
Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA.
2
Department of Biochemistry and Molecular Biology, School of Medicine, University of Murcia and IMIB-Arrixaca, Murcia, Spain.
3
Institute of Molecular Biology & Biotechnology, Bahauddin Zakariya University, Multan, Pakistan.
4
Molecular Biology & Genetics Department, Medical Research Center, Liaquat University of Medical & Health Sciences, Jamshoro, Pakistan.
5
Institute of Pharmaceutical Sciences, University of Veterinary & Animal Sciences, Lahore, Pakistan.
6
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
7
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
8
Yale Center for Genome Analysis, Yale University, West Haven, CT, USA.

Abstract

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

PMID:
26197705
PMCID:
PMC4609612
DOI:
10.1111/pcmr.12400
[Indexed for MEDLINE]
Free PMC Article

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