Precocious Puberty Gene Found

The storybook character Peter Pan may have escaped the fate, but in the real world growing up is inevitable.

Biologically speaking, the turn to adulthood happens in humans when the brain tells the pituitary glands to start producing hormones, jump-starting puberty. This typically happens around age 10 in girls and 11 in boys. But, for a small percentage of children, the process can start much earlier. If the brain initiates the process before age 8 in girls or 9 in boys, the child experiences central precocious (or “early”) puberty.

Though early puberty has become more common in recent years, the causes of this unsettling condition have remained unclear. Last week, however, a team of scientists from the Broad Institute, Boston Children’s Hospital, Brigham and Women’s Hospital, and the University of São Paulo in Brazil announced a breakthrough in an article published in the New England Journal of Medicine: they identified a gene, MKRN3, that causes some cases of central precocious puberty.

The team isolated the gene by analyzing whole-exome sequencing data – the genetic code from the protein-coding regions of the genome – of 40 individuals from 15 different families affected by central precocious puberty. The families had been selected because each had multiple family members with the condition. In analyzing the sequencing data, the researchers found mutations in MKRN3 in family members from 5 of the 15 families. In each case, the mutation prevents the gene from functioning normally, suggesting that, if MKRN3 isn’t working properly, puberty starts early in the affected individuals.

“Finding this common pattern was exciting evidence that mutations in MKRN3 lead to precocious puberty. We never thought a single gene was going to cause a third of the familial cases that we were studying,” said Broad researcher and paper co-author Andrew Dauber. Dauber is a pediatric endocrinologist at Boston Children’s Hospital and works in the lab of Broad senior associate member Joel Hirschhorn, who was also a co-author of the study.

An interesting twist to the finding is that MKRN3 is an imprinted gene. At conception, individuals inherit copies of each gene from both parents and, in most cases, both the maternal and paternal copies of the gene work equally. However, in imprinted genes, only the copy from a specific parent is expressed; the other is silenced by biochemical activity during the assembly of its DNA. In MKRN3, only the copy inherited from the father is expressed.

“What that means is that, if you have a faulty copy of MKRN3, who you inherited it from dictates whether or not you’ll have early puberty. If you inherited the mutation on the copy from your mother, you will carry it but will not be affected. However, if you have a loss of function in the copy of MKRN3 that you inherit from your father, then you will have early puberty.”

That means that the condition can skip generations, or that cousins can be affected even if their parents are not. Dauber said that all of the cases the team found in their study fit MKRN3’s imprinted genetic pattern.

Dauber credited the Broad’s genome sequencing and analysis tools and support team for helping them make the discovery.

“That aspect of the study was clearly empowered by the unbelievable work of the Genomics Platform and the Genome Sequencing and Analysis Group in the Broad’s Medical and Population Genetics program, which supports the Genome Analysis Toolkit (GATK). They gave us amazingly good quality sequencing data with rich annotations, and support through the whole genome analysis pipeline.”

A second part of the study was completed at Brigham and Women’s Hospital, where senior author Ursula Kaiser and colleagues tested the connection between MKRN3 and puberty onset by measuring MKRN3 expression in the brains of mice. They found that expression levels of MKRN3 decreased dramatically immediately before puberty and remained low after puberty, supporting the idea that MKRN3 affects the timing of puberty by suppressing its onset.

Dauber said that the research team cannot say what percentage of central precocious puberty cases are instigated by MKRN3, since their study carefully selected families with clear hereditary patterns in order to increase the chance of finding a genetic link to the condition. However, he believes that the finding will ease the minds of patients and parents in those cases in which MKRN3 does prove to be the culprit.

“People come into the clinic asking: could it be the lotion I’m using, or did I take too many hormones, or should I be eating organic foods? These are all reasonable questions,” Dauber said. “Because of this finding, we’ll be able to give some people reassurance that they could not have prevented central precocious puberty – that it didn’t result from something they did or did not do.”