MKRN3 mutations in familial central precocious puberty.

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.