Thr40 and Met122 are new partial loss-of-function natural mutations of the human melanocortin 1 receptor.
Jiménez-Cervantes. C C; Germer. S S; González. P P; Sánchez. J J; Sánchez. C O CO; García-Borrón. J C JC
Key Findings
- Ile40Thr and Val122Met are natural MC1R mutations that reduce receptor activity
- Val122Met binds the melanocortin ligand with lower affinity than normal MC1R
- Both variants show weaker cAMP signaling, leading to poorer melanin production
Practical Outcomes
- If you plan to use melanotan‑I for tanning or skin protection, consider that individuals with these MC1R variants may see limited results and should be cautious about UV exposure. Genetic testing (or family skin type clues) can help predict response and guide safer dosing or alternative strategies.
Summary
The study found two common genetic variants of the skin‑color receptor MC1R (Ile40Thr and Val122Met) that don’t respond as well to melanocortin signals, meaning people with these variants tan less and may have higher skin‑cancer risk. This matters for anyone using melanotan‑I, a peptide that works by activating MC1R, because the drug may be less effective for them.
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.
Study Information
pubmed
2001
2001-11-09T00:00:00.000Z
10.1016/s0014-5793(01)03025-3