Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort

Abstract

Mutations in the melanocortin 4 receptor gene ( MC4R ) are associated with obesity but little is known about the prevalence and impact of such mutations throughout human growth and development. We examined the MC4R coding sequence in 5724 participants from the Avon Longitudinal Study of Parents and Children, functionally characterised all non-synonymous MC4R variants and examined their association with anthropometric phenotypes from childhood to early adulthood. The frequency of heterozygous loss of function (LoF) mutations in MC4R was ~1/337 (0.30%), considerably higher than previous estimates. At age 18 years, mean differences in body weight, body mass index and fat mass between carriers and non-carriers of LoF mutations were 17.76kg (95% CI: 9.41, 26.10), 4.84kg/m 2 (95% CI: 2.19, 7.49) and 14.78kg (95% CI: 8.56, 20.99), respectively. MC4R LoF mutations may be more common than previously reported and carriers of such variants may enter adult life with a substantial burden of excess adiposity.

Identification of p.Met215Ile mutation of the MC4R gene in a Moroccan woman with obesity

“… 34 Recently, this variant was also identified in one case from 5724 participants of a specific Avon Longitudinal Study of Parents and Children (ALSPAC) UK Birth Cohort. 35 All carriers were heterozygous for this rare mutation. This variant is considered codominant with incomplete penetrance and variable expressivity.…”

“…The p.Met215Ile is located in the TM5 of the MC4R. 35 The TMs have been identified as essential for ligand binding and signaling pathways mediated by the MC4R receptor for the regulation of appetite and metabolism. In the MC4R gene, some mutations can induce reduced/abolished α‐MSH binding or altered intracellular signaling cascades.…”

“…Some functional assays were performed to analyze the surface expression of the receptor, the response of cAMP to agonist binding, and the activation of ERK/MAPK signaling. 33 , 34 , 35 Herrfurth et al reported that this variant reduced cell surface expression by 80% compared to the wild‐type receptor. 33 The ligand‐activated cAMP accumulation was reduced following binding to NDP‐α‐MSH (a synthetic analog of α‐MSH) and required a 10‐fold higher concentration of α‐MSH compared to the wild‐type receptor.…”

“… 33 The ligand‐activated cAMP accumulation was reduced following binding to NDP‐α‐MSH (a synthetic analog of α‐MSH) and required a 10‐fold higher concentration of α‐MSH compared to the wild‐type receptor. 33 , 34 , 35 In fact, the mutation resulted in reduced MC4R activity. It induced a 39.6% decrease in maximal signaling compared to wild‐type MC4R signaling.…”

“… 33 Also, Wade et al demonstrated that this variant showed impaired β‐arrestin‐2 coupling. 35 As we know, the β‐arrestins are major regulators of MC4R‐mediated signaling processes and play an important role in the regulation of energy homeostasis.…”