This article is a collaboration between MedPage Today® and:
Findings of a genetic mutation apparently causing precocious puberty in some children may help researchers decipher the longstanding mystery of what triggers puberty, a new study suggested.
Genome sequencing of 40 members of 15 families in which one member was diagnosed with central precocious puberty revealed four mutations in the MKRN3 gene, according to Ana Claudia Latronico, MD, PhD, of the University of São Paulo in Brazil, and colleagues.
Lab studies indicated that expression of the corresponding gene in mice was high in the arcuate nucleus prior to puberty, then fell and stayed low when puberty commenced, they reported online in the New England Journal of Medicine.
Collectively, the results suggested that this gene plays a key role in the timing of sexual maturation -- acting as a brake on puberty during childhood, in the words of an accompanying editorial by Ieuan A. Hughes, MD, of the University of Cambridge in England.
But plenty of mystery still surrounds the timing of puberty, Hughes noted.
"An explanation of why puberty starts at about the time of the junction of the first and second decades of human life has yet to be had. How MKRN3, an exemplar of a neurobiologic brake, interacts with other major players of puberty, such as kisspeptin, gonadotropin releasing hormong, leptin, and a host of neurotransmitters (excitatory and inhibitory), will certainly continue to exercise the minds of the puberty pundits," he wrote.
In the study, Latronico and colleagues identified 15 patients with central precocious puberty, defined as clinical and laboratory signs of puberty onset prior to age 8 in girls and age 9 in boys.
The researchers obtained blood samples from them and from 25 family members, including parents, grandparents, siblings, and other close relatives. In all, precocious puberty was currently or previously diagnosed in 32 of these individuals.
These individuals were all found to have one of four heterozygous mutations in MKRN3, including three frameshift mutations and one missense mutation.
All individuals with precocious puberty had inherited the mutation from their fathers, which was expected since MKRN3 is an "imprinted" gene that is expressed only from the paternally inherited allele, Latronico and colleages indicated.
One participant had such a mutation but was asymptomatic; that individual had inherited the mutated allele from the mother.
The researchers also examined expression of the murine MKRN3 gene in six mice as they grew from pups into adults. They found that expression decreased rapidly as puberty began, at about postnatal day 15, and then remained low thereafter up to age 45 days.
That MKRN3 would play a role in sexual maturation is not a surprise, according to the study investigators and to Hughes.
Latronico and colleagues noted that the gene is associated with ubiquitination, the proccess of tagging intracellular proteins for digestion in the proteasome. This same process can also trigger signal transduction, cell differentiation, and other processes unrelated to cellular housekeeping.
Such a function could plausibly be connected to gonadotropin releasing hormone (GnRH) activitation, the researchers indicated, although the exact mechanism "remains to be elucidated."
Hughes concurred, writing that the study "appears to cement the idea that puberty starts only with the release of a restraint mechanism on the GnRH pulse generator, which in turn releases the brake on puberty."
But neither the study team nor Hughes suggested a means of exploiting such findings to treat precocious puberty, whether or not it involves MKRN3 mutations.
The study also did not address the prevalence of such mutations in the general population or estimate the percentage of precocious puberty cases that may arise from them versus other causes.
The study was funded by the National Institutes of Health and several Brazilian government agencies and foundations.
Study authors reported relationships with Ferring, Pfizer, Correlagen, Merck Serono, and Sandoz. Hughes declared he had no relevant financial interests.
- Reviewed by F. Perry Wilson, MD, MSCE Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner
New England Journal of MedicineSource Reference: Abreu A, et al "Central precocious puberty caused by mutations in the imprinted gene MKRN3" New Engl J Med 2013; DOI: 10.1056/NEJMoa1302160.
New England Journal of MedicineSource Reference: Hughes I "Releasing the brake on puberty" New Engl J Med 2013; DOI: 10.1056/NEJMe1306743.