Three of the four mutations identified in MKRN3 in our series were frameshift mutations resulting in premature stop codons, whereas the fourth, a missense variant (p.Arg365Ser), is predicted to interfere with protein function (Fig. 2). The arginine at position 365 is located in the C3HC4 RING domain responsible for the ubiquitin ligase activity and is evolutionarily highly conserved (Fig. 2). Definitive confirmation that this missense variant causes loss of function awaits the availability of a functional assay. Although the function of MKRN3 is not well understood, and the mechanism by which MKRN3 mutations result in early activation of the central reproductive axis are not yet known, our genetic data are sufficiently compelling and statistically strong to invoke a causative role for MKRN3 in central precocious puberty.
