ESPE Abstracts (2015) 84 P-1-121

ESPE2015 Poster Presentations Poster Category 1 Puberty (11 abstracts)

A Missense Mutation in MKRN3 in a Danish Girl with Central Precocious Puberty and Her Brother with Early Puberty

Johanna Känsäkoski a, , Taneli Raivio a, , Anders Juul c & Johanna Tommiska a,

aPhysiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; bChildren’s Hospital, Helsinki University Hospital, Helsinki, Finland; cDepartment of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

Background: Idiopathic central precocious puberty (ICPP) results from the premature reactivation of the hypothalamic-pituitary-gonadal axis leading to development of secondary sexual characteristics prior to 8 years in girls or 9 years in boys. Mutations in the maternally imprinted MKNR3 gene are the most common identified genetic cause of ICPP to date. Expression of MKRN3 in the arcuate nucleus is presumed to be inhibitory to GnRH secretion, but the exact mechanism remains unknown.

Objective and hypotheses: We wanted to investigate whether mutations in MKRN3 contribute to the premature onset of puberty in Danish ICPP patients. We also wanted to find out if MKRN3 is expressed in adult human hypothalamus.

Method: We screened 29 Danish girls with ICPP for mutations in MKRN3 by Sanger-sequencing. Expression of MKRN3 in a human hypothalamic cDNA library was investigated by PCR and gel electrophoresis.

Results: We identified one paternally inherited variant (c.1034G>A (p.Arg345His)) in MKRN3 in one girl with ICPP and in her brother with early puberty. The variant was predicted to affect protein function by all three prediction programs used, and it has been reported once in 4 300 individuals in the European American population in the NHLBI ESP database. Expression of MKRN3 was confirmed in the hypothalamic cDNA library.

Conclusion: Our results are in line with previous studies where paternally inherited MKRN3 mutations have been found both in males and females with ICPP or early puberty. Our report further expands the set of MKRN3 mutations identified in ICPP patients across diverse populations. Expression of MKRN3 in adult human hypothalamus is in contrast to previous findings in the mouse arcuate nucleus and suggests MKRN3’s hypothalamic function is not limited to inhibition of GnRH secretion.

Funding: This work was supported by the Academy of Finland, the Helsinki University Central Hospital Research Funds, Foundation for Pediatric Research, the Danish research council (AJ), and the Capital Region of Copenhagen (AJ).

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