<b><i>MKRN3</i></b> Mutations in Familial Central Precocious Puberty

Abstract

Loss-of-function mutations in the gene encoding the makorin RING finger protein 3 (MKRN3) have recently been reported to underlie familial cases of central precocious puberty (CPP). The imprinted MKRN3 gene is expressed only from the paternal allele, and mutations inherited from the father affect boys and girls equally, which is in contrast to the known female preponderance in idiopathic CPP. By screening a series of 6 families and 1 male patient with idiopathic CPP, we identified 2 further families carrying loss-of-function mutations in MKRN3, the previously reported variant c.475_476insC (p.Ala162Glyfs*14) and a novel one, c.331G>T (p.Glu111*). We conclude that MKRN3 mutations appear to be a frequent cause of familial CPP and, considering the imprinted mode of inheritance, may also account for a certain proportion of isolated CPP cases. Remarkably, four out of six MKRN3 mutations described so far encode either a stop codon or a frameshift followed by a premature stop codon. Consequently, there may be less severe mutations that possibly associate with more subtle phenotypes, which could even explain variation within the physiological range. Mutation screening in larger cohorts is necessary in order to estimate the real prevalence of MKRN3 mutations in idiopathic CPP.

Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty

“…1), and these findings are consistent with published data. Indeed, the offspring of the 15 previously reported fathers with MKRN3 mutations (11,12,13,14,15) consists of 25 girls and six boys, consistent with the imbalance in the numbers of boys and girls observed in We compared phenotypes in girls with and without MKRN3 mutations, to determine whether, in addition to familial history, there were any clinical or biological features suggestive of MKRN3 mutation. Median age at puberty onset was the only parameter found to differ significantly between girls with and without mutations (lower in girls with mutations, at 6.0 years (5.4-6)).…”

“…These mutations were found in 15 patients from five families. Thirteen other patients with iCPP and MKRN3 mutations, from six families, have since been described (12,13,14,15). In our study, heterozygous MKRN3 mutations were found in 14 of 46 index patients with iCPP (30%).…”

“…Median age at puberty onset was the only parameter found to differ significantly between girls with and without mutations (lower in girls with mutations, at 6.0 years (5.4-6)). Similarly, the median age at puberty onset in 22 previously reported cases in girls was 6.0 years (5.4-6.1) (11,12,13,14,15). The narrow range of age at puberty onset in patients with MKRN3 mutations indicates that the activity of the encoded protein is critical at a specific time point in the postnatal development of the GnRH neuronal network.…”

“…This may reflect a recruitment bias and the well-known higher prevalence of precocious puberty in girls than in boys. No accurate information about age at puberty onset was available for three previously reported cases of iCPP in male patients with MKRN3 mutations (11,12,13). The other five boys had a median age at Tanner stage 2 of 8.25 years (8-8.5), suggesting that the decrease in age at puberty onset was smaller for boys than for girls.…”

“…The mutation was inherited from the father in all 15 cases, consistent with the maternal imprinting of MKRN3. Other loss-of-function MKRN3 mutations have since been reported (12,13,14,15). MKRN3, located on chromosome 15q11.2, in the critical region for Prader-Willi syndrome, encodes MKRN3 protein.…”