MC3R mutations linked to the time of puberty


People with loss-of-function mutations in MC3R later have the onset of puberty, the researchers discovered.

Over 800 females wearing a MC3R The mutation was 4.7 months behind in age at menarche compared to non-carriers, reported Stephen O’Rahilly, MD, of the University of Cambridge in England, and colleagues.

In addition, mutations in MC3R were associated with late voice breakdown in men; lower lean body mass; and lower levels of insulin-like growth factor 1 (IGF1), which regulates growth hormone and the onset of puberty, they noted in Nature.

The MC3 receptor is one of a group of receptors in the brain that control growth and eating, among other functions. The MC4 receptor, a cousin of MC3, has been a target for obesity scientists because it controls appetite and energy consumption.

The age at which children enter puberty has become younger over time. A 2020 study estimated that girls enter puberty a full year earlier than in the 1970s. Earlier studies have linked the early onset of puberty to increased body mass and over-nutrition. .

This study provided a genetic explanation for this observed trend. “By proposing a hitherto unrecognized role for MC3R in the hypothalamus, the work of Lam and colleagues brings us closer to understanding the central mechanisms involved in global trends towards height increase and decrease in body size. ages at the onset of puberty that have been observed over the past century, ”wrote Alejandro Lomniczi, PhD, of Oregon Health and Science University in Portland, in an accompanying editorial.

This study could also have clinical applications, the study authors suggested. “Analysis of the MC3R should be part of the routine genetic analysis of patients with delayed puberty, short stature and low levels of IGF1, “they wrote.” Our data suggest the potential utility of MC3R agonists in some patients with delayed puberty and / or short stature and also potentially in sarcopenia, a condition in which low lean body mass, including muscle, contributes to the disability of various chronic disorders. “

O’Rahilly and his colleagues found that out of 200,000 British biobank volunteers, 0.82% carried a deleterious mutation of MC3R uncomfortable. They isolated three variants associated with delayed puberty in women and men, one of which – p.F45S – was associated with a 5.16 month delay in age of menarche.

“This is the most important effect on the time of puberty associated with a single variant identified in a [genome-wide association study] so far, ”Lomniczi noted.

The researchers then analyzed two other databases – the Avon Longitudinal Study of Parents and Children (ALSPAC), which tracks nearly 6,000 participants from birth to 18, and the Genes & Health study, which focuses on people of South Asian descent in England.

In ALSPAC, only six people with heterozygous mutations in the MC3R gene have been identified. No significant delay in the onset of puberty was observed in these six participants, according to O’Rahilly and his team.

In the Genes & Health cohort, a Bangladeshi man carrying a homozygous mutation in the MC3R gene has been identified. He said he entered puberty very late, not having started until his early twenties. He was small, nearly three standard deviations below the WHO benchmark average height, and his height-to-seat ratio was below the normal range for South Asians. He also had reduced levels of IGF1.

The researchers also confirmed their findings using mice. Mc3r knockout mice showed a 2 day delay in the onset of sexual maturation compared to wild type mice. When both groups were fasted, the knockout mice ‘reproductive cycle was unaffected, while the estrus cycle in wild-type mice was twice as long.

“The striking insensitivity of MC3R-deficient mice to the reproductive impact of a fasting period and the evidence that these mice delayed sexual maturation indicate conservation of this biology across species,” wrote O’Rahilly and these partner’work.

“Although these data cannot confirm a causal role of MC3R in puberty and growth, they support a potential role of this receptor in the regulation of puberty onset, body growth and IGF1 levels”, Lomniczi noted.

  • Lei Lei Wu is a news intern for Medpage Today. She is based in New Jersey. To follow


O’Rahilly said he has been a consultant for Pfizer, AstraZeneca, GlaxoSmithKline and ERX Pharmaceuticals.

A co-author reported an unrestricted research grant from Alnylam Pharmaceuticals.

Lomniczi has declared no conflict of interest.

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