In our analysis of whole-exome–sequencing data in 40 members of 15 families with central precocious puberty, we identified a single gene, MKRN3, encoding the makorin RING-finger protein 3, with variants predicted to be deleterious in 5 families. MKRN3 is an intronless gene located on chromosome 15q11.2, in the Prader–Willi syndrome critical region.35 This gene is maternally imprinted, and only the paternal allele is expressed.35 The makorin protein family is distinguished by a characteristic combination of zinc-finger motifs; these proteins include two or three copies of a C3H motif in the N-terminal, followed by a novel Cys–His configuration, a C3HC4 RING zinc finger, and a final C3H motif.36 C3H zinc-finger motifs have been implicated in RNA binding, whereas the RING zinc-finger motif is found in most E3 ubiquitin ligases and is responsible for ubiquitin-ligase activity.37 The widespread species conservation of the makorin protein family suggests that it plays one or more vital roles in cells, with high levels of expression in the developing nervous system.36 MKRN3, on the other hand, is conserved only in therian mammals, and its precise function has not yet been determined.37
