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Identification and functional characterization of natural human melanocortin 1 receptor mutant alleles in Pakistani population
Author(s) -
Shahzad Mohsin,
Sires Campos Julia,
Tariq Nabeela,
Herraiz Serrano Cecilia,
Yousaf Rizwan,
JiménezCervantes Celia,
Yousaf Sairah,
Waryah Yar M.,
Dad Haseeb A.,
Blue Elizabeth M.,
Sobreira Nara,
LópezGiráldez Francesc,
Kausar Tasleem,
Ali Muhammad,
Waryah Ali M.,
Riazuddin Saima,
Shaikh Rehan S.,
GarcíaBorrón José C.,
Ahmed Zubair M.
Publication year - 2015
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12400
Subject(s) - melanocortin 1 receptor , melanocortin 3 receptor , biology , hek 293 cells , allele , receptor , mutant , agonist , melanocortin receptor , mutation , nonsense mutation , signal transduction , microbiology and biotechnology , missense mutation , genetics , endocrinology , gene
Summary Melanocortin 1 receptor ( MC 1R), 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, MC 1R 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 MC 1R 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 HEK 293 cells. p.Tyr298* MC 1R 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.