title: Thr40 and Met122 are new partial loss-of-function natural mutations of the human melanocortin 1 receptor.
abstract: Activation by melanocortins of the melanocortin 1 receptor (MC1R), expressed in epidermal melanocytes, stimulates melanogenesis. Human MC1R gene loss-of-function mutations are associated with fair skin, poor tanning and increased skin cancer risk. We identified two natural alleles: Ile40Thr, probably associated with skin types I-II, and Val122Met. Val122Met bound [(125)I][Nle(4), D-Phe(7)]-alpha-melanocyte stimulating hormone with lower affinity than the wild-type. Dose-response curves of cAMP accumulation were right-shifted for both forms. The Val122Met form failed to achieve maximal cAMP responses comparable to the wild-type or Ile40Thr receptors. Thus, the Ile40Thr and Val122Met variants are partial loss-of-function natural mutations of MC1R.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Murcia, Apto 4021, 30100 Espinardo, Murcia, Spain. celiajim@um.es
authors.forename: C
authors.initials: C
authors.lastname: Jiménez-Cervantes
authors.forename: S
authors.initials: S
authors.lastname: Germer
authors.forename: P
authors.initials: P
authors.lastname: González
authors.forename: J
authors.initials: J
authors.lastname: Sánchez
authors.forename: C O
authors.initials: CO
authors.lastname: Sánchez
authors.forename: J C
authors.initials: JC
authors.lastname: García-Borrón
mesh_terms: D000483:Alleles; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D002460:Cell Line; D016895:Culture Media, Serum-Free; D000242:Cyclic AMP / Q000378:metabolism; D014644:Genetic Variation; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D018043:Receptors, Corticotropin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D044101:Receptors, Melanocortin; D012880:Skin Pigmentation; D014162:Transfection; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D016588:Anticarcinogenic Agents; D016895:Culture Media, Serum-Free; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-; D000242:Cyclic AMP