Identification and functional characterization of natural human melanocortin 1 receptor mutant alleles in Pakistani population |
| |
| Authors: | Cecilia Herraiz Serrano Rizwan Yousaf Celia Jiménez‐Cervantes Sairah Yousaf Yar M Waryah Haseeb A Dad Elizabeth M Blue Nara Sobreira Francesc López‐Giráldez Tasleem Kausar Muhammad Ali Ali M Waryah Saima Riazuddin Rehan S Shaikh Zubair M Ahmed |
| |
| Institution: | 1. Department of Biochemistry and Molecular Biology, School of Medicine, University of Murcia and IMIB‐Arrixaca, Murcia, Spain;2. Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA;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: | melanocortin 1 receptor melanocytes cAMP signaling hypopigmentation |
|
|
