For a small subset of boys and girls who undergo early puberty, there’s now a specific explanation. New genetic research, involving whole-exome sequencing, has identified four novel heterozygous mutations in a gene known as MKRN3. Interestingly, while precocious puberty is more common in girls, all 15 affected children in the study inherited the mutations from their fathers.
Precocious puberty—the development of secondary sexual characteristics before 8 years in girls and 9 years in boys—has been associated with short stature, long-term health risks and an increase in conduct and behavioral disorders during adolescence. Physiologically, there are two types: central and peripheral. Central, the more common form, occurs when the pituitary gland, which controls puberty development, is activated too early.
“While a great deal of genetic studies have focused on the overall genetic contribution to pubertal timing, far less research has been conducted to find specific genetic causes of central precocious puberty,” says Andrew Dauber, MD, MMSc, of the Division of Endocrinology at Boston Children’s Hospital, who co-authored the study, published online this week by The New England Journal of Medicine.
To better understand this condition, Dauber and his collaborators, including Ana Claudia Latronico, MD, PhD, of the University of Sao Paulo, and Ursula Kaiser, MD, of the Brigham and Women’s Hospital, had previously sought genetic causes for precocious puberty by assessing known candidate genes.
However, for this study, the researchers took a genome-wide approach and performed whole-exome sequencing analysis on 40 individuals from 15 families with central precocious puberty. Over the years, the researchers had collected detailed clinical and biochemical data on these families.
“With this large sampling of multi-generations of family members, we thought we could find at least some of the genetic causes of familial precocious puberty,” Dauber says. “Prior to the whole-exome sequencing analysis, Drs. Latronico and Kaiser knew a great deal about their physiology, but not the genetic cause.”
Instead of assessing one gene at a time, whole-exome sequencing allows researchers to examine all the protein-coding genes in the genome. “Humans have approximately 20,000 to 30,000 genes in their genome, and this type of analysis allows researchers to sequence all of these genes at once, focusing only on the parts of the genes that code for the building blocks of the proteins,” says Dauber.
In five of the 15 families, the researchers identified four mutations in the MKRN3 gene, which encodes a protein that is thought to help tag other proteins for degradation. The genetic mutations truncated the protein, disrupting its function. “The affected families had frame-shift mutations, which are more extreme and incredibly rare,” Dauber says. “The extremely rare nature of these mutations, which were found in all the affected families, reassures us about the validation of our findings.”
Importantly, a child only needs one copy of an MKRN3 mutation to develop central precocious puberty. Moreover, all the affected children inherited the mutation from their fathers—even if the father did not have early puberty (indicating that he inherited the mutation from his mother). Dauber explains: “This is one of the very few genes in the genome that is imprinted, where the gene knows if it was inherited from the mother or father’s chromosome,” he says. “In this case, the mutation gets expressed only if it is inherited from the sperm.”
Central precocious puberty has been reported to occur mostly in girls, but of the 15 affected patients with MKRN3 mutations, seven were male. In contrast, in the 10 families without MKRN3 mutations, all affected family members were female.
How MKRN3 mutations lead to early pituitary-gland activation is still unknown, but screening for mutations of MKRN3 in sporadic cases of central precocious puberty could add information about the gene’s role in pubertal timing.
The researchers also point out that their findings aren’t restricted to a specific ethnic group, because the patients were of American, Brazilian and European lineage.
“Our research is going to open the door for an entirely new understanding of what controls the timing of puberty,” Dauber says. “It also will allow doctors to diagnose the cause of precocious puberty in a subset of patients.”
Boston Children’s Hospital, the National Institutes of Health and research funding agencies in Brazil supported the study.