ESPE Abstracts

Background: Central precocious puberty (CPP) is often familial but its genetic cause is largely unknown. Very recently, the makorin RING finger protein 3 (MKRN3) gene has been found mutated for the first time in 5 families with familial precocious puberty. The inheritance pattern is particular being the MKRN3 a maternal imprinted gene. Moreover in a recent genome wide association study common intronic or intragenic variants harbouring this gene and other two imprinted genes, DLK1 and KCNK9, have been associated to age at menarche, demonstrating parent-of-origin-specific associations concordant with known parental expression patterns.

Objective and hypotheses: Here, we investigated mutations in MKRN3, DLK1 and KCNK9 in a cohort of 60 girls with CPP.

Method: We studied 60 Italian children with CPP (all girls, mean age 6.8±1.8 years, 37% familial cases, normal brain MRI). The coding regions of MKRN3, DLK1 and KCNK9 were sequenced.

Results: Genetic analysis revealed two already described mutations (Pro160Cysfs*14 and Arg328Cys) in MKRN3 in two unrelated girls, one with familiar CPP and one apparently sporadic respectively. No rare variants were found in DLK1 and KCNK9 genes. One already described synonymous variants in KCNK9 and 8 in DLK1 were found.

Conclusion: We confirm that MKRN3 gene mutations represent a rather frequent cause of CPP in girls, even if different prevalence of mutation can depend on characteristics and selection criteria of patients studied (such as age at onset of CPP or definition of familiarity for CPP). We investigated for the first DLK1 and KCNK9 in CPP and our results do not support a role for mutations in the coding region of these two genes in the etiology of CPP. Involvement of these genes in regulation of pubertal timing in humans warrants further investigation.