ESPE Abstracts

Background: Mutations in the imprinted gene MKRN3 have been associated with inherited central precocious puberty (CPP). MKRN3 is a maternal imprinted gene and the disease is exclusively paternally transmitted in an autosomal dominant manner. Although the mechanism is unclear, it has been suggested that MKRN3 inhibits hypothalamic GnRH release, leading to a loss-of-function mutation and CPP. To date, more than 20 MKRN3mutations have been reported.

Methods: Six patients (3M, 3F) with CPP from highly consanguineous families were enrolled. MKRN3 was sequenced for the proband and the identified mutation was screened in 13 family members.

Results: CPP was diagnosed based on clinical and hormonal findings in 6 children belonging to 2 related families. Five were treated with GnRH analog. The age of pubertal onset in the girls ranged from 5 to 6.5 years and in the boys, from 7 to 8 years. The familial occurrence of CPP raised the diagnosis of MKRN3 mutation; MKRN3 sequencing revealed a novel heterozygous loss-of-function missense mutation, c.1033C>T; p.Arg345Cys. This mutation is located within a zinc finger motif predicted to be involved in RNA binding, essential for protein function. Nine family members were heterozygous for the identified mutation, including 2 parents of family 1 and the father of family 2. Two children of family 1 were homozygous for the same mutation inherited both maternally and paternally. Two non-affected members were negative.

Conclusions: We report a novel MKRN3 mutation in highly consanguineous families with multiple cases of CPP. This is the first report of homozygosity for an MKRN3 mutation, indicating that the phenotype in these cases does not differ from the phenotype of heterozygous patients. MKRN3 sequencing is recommended in familial CPP.