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Exome Sequencing Study Reveals Apparent Culprit in Early Puberty Condition

NEW YORK (GenomeWeb News) – A new study suggests one form of precocious puberty may occur as a consequence of mutations to a maternally imprinted, paternally expressed gene called MKRN3.

Reporting in the New England Journal of Medicine online last night, researchers from Brigham and Women's Hospital, Boston Children's Hospital, the Broad Institute, the University of Sao Paulo, and elsewhere described the whole-exome sequencing strategy that they used to unearth suspicious mutations in the makorin RING-finger protein 3 coding gene — now suspected of inhibiting pathways that release puberty-promoting hormones.

Without exception, the team found that MKRN3 alterations were inherited from the affected individual's father, consistent with MKRN3's paternal expression patterns.

"These findings will open the door for a new understanding of what controls the timing of puberty," co-senior author Ursula Kaiser, endocrinology, diabetes, and hypertension division chief at Brigham and Women's Hospital, said in a statement.

That, in turn, may improve the diagnosis and detection of precocious puberty in some individuals, she added, particularly those from families affected by the condition.

Beyond those applications, Kaiser noted that an enhanced understanding of MKRN3's role in puberty timing might ultimately help in putting together a more complete picture of the process and the biological and environmental factors influencing it.

Children with the form of early puberty that Kaiser and her colleagues focused on — called central precocious puberty or gonadotropin-dependent precocious puberty —typically start manifesting signs of secondary sexual characteristics before they're eight or nine years old. Past studies suggest that central precocious puberty includes premature activity by the hypothalamus, pituitary gland, and gonadotropin releasing hormone, researchers noted.

The reason for that activity remains mysterious, though it's believed that genetic, environmental, and nutritional factors can all influence puberty's onset. The timing of puberty tends to correspond with other behavioral traits and disease risk patterns, too, sparking even more interest in the genetics of this process.

For instance, the authors of the new study noted, any early start to menstruation in girls tends to coincide with obesity later in life, as well as diseases such as breast cancer, ovarian cancer, type 2 diabetes, and heart disease.

Some genetic contributors to other puberty-related conditions have already been unearthed through candidate gene studies, they added, though few with proposed ties to the central precocious form have turned up so far.

To expand that search, the researchers used the Agilent SureSelect Human All Exon Kit v2, coupled with Illumina's HiSeq 2000 instrument, to do whole-exome sequencing on 40 individuals — members of 15 different families affected by central precocious puberty.

Among the individuals tested were 27 females who'd began puberty before their eighth birthday and five males showing signs of puberty by the time they were nine years old. The remaining five females and three males went through puberty with typical timing.

When the team delved into the exome sequence data, it tracked down precocious puberty-associated MKRN3 mutations in one-third of the families, unearthing four different loss-of-function or damaging mutations in the gene in all.

Within the five families carrying these mutations, researchers saw MKRN3 alterations in eight females who'd started puberty between the ages of five and six-and-a-half years old. Mutations in the gene also turned up in seven males whose puberty began when they were six to eight-and-a-half years old.

The team's follow-up experiments, including quantitative real-time PCR-based tests of MKRN3 levels in maturing young mice, suggest that a MKRN3 mutation may staunch the release of gonadotropin-releasing hormone — a puberty inhibitory role appears to be compromised in individuals with certain genetic hiccups in the gene.

Study authors also noted that MKRN3 falls in the vicinity of chromosome 15 genes implicated in Prader Willi syndrome, a condition characterized by stunted sexual development and marked obesity, among other features. So far, though, there is no evidence that MKRN3 itself contributes to that condition.

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