title: Circulating MKRN3 levels decline prior to pubertal onset and through puberty: a longitudinal study of healthy girls.
abstract: BACKGROUND
  Puberty is initiated by a complex interaction of suppressing and stimulating factors. Genetic studies of familial central precocious puberty have suggested makorin ring finger protein 3 (MKRN3) as a major inhibitor of GnRH secretion during childhood. Furthermore, genetic variation near MKRN3 (rs12148769) affects age at menarche in healthy girls.
  
  
  OBJECTIVE
  The purpose of this study was to evaluate whether serum levels of MKRN3 declined before pubertal onset in healthy girls.
  
  
  METHODS
  This was a population-based longitudinal study of healthy Danish girls and a cohort study of early maturing girls.
  
  
  METHODS
  The study was performed in the general community and in a tertiary referral center for pediatric endocrinology.
  
  
  METHODS
  Healthy girls (n = 38) aged 9.3 years (range, 5.9-11.3 years) at baseline and followed for 6.0 years (2.7-7.6 years) (2006-2014) with blood sampling every 6 months and early maturing girls (n = 13) with breast development ay <8.3 years of age were included.
  
  
  METHODS
  Serum levels of MKRN3 were measured in 354 samples (median, 9 per girl; range, 2-14 per girl), and genotyping of variants near MKRN3 (rs12148769 and rs12439354) was performed.
  
  
  RESULTS
  MKRN3 concentrations declined preceding pubertal onset; the geometric mean (95% confidence interval) 3 years before pubertal onset vs the last visit before pubertal onset was 304 pg/mL (264-350 pg/mL) vs 257 pg/mL (243-273 pg/mL), corresponding to a reduction of 15% (1-27%) (P = .033). In prepubertal girls, circulating MKRN3 correlated negatively with gonadotropin levels: for FSH, r = -0.262 (P = .015) and for LH, r = -0.226 (P = .037). After adjustment, MKRN3 levels were lower in early maturing girls than in age-matched prepubertal girls: 171 pg/mL (<25-333 pg/mL) vs 262 pg/mL (94-624 pg/mL) (P = .051). Genetic variants near MKRN3 did not correlate with serum levels of MKRN3.
  
  
  CONCLUSIONS
  Declining levels of circulating MKRN3 preceded pubertal onset. The negative correlation between MKRN3 and gonadotropins further supports MKRN3 as a major regulator of hypothalamic GnRH secretion during childhood. Undetectable or low MKRN3 levels were observed in a subgroup of patients with early onset of puberty.
authors.affiliation: Department of Growth and Reproduction, EDMaRC, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: Casper P
authors.initials: CP
authors.lastname: Hagen
authors.forename: Kaspar
authors.initials: K
authors.lastname: Sørensen
authors.forename: Mikkel G
authors.initials: MG
authors.lastname: Mieritz
authors.forename: Trine Holm
authors.initials: TH
authors.lastname: Johannsen
authors.forename: Kristian
authors.initials: K
authors.lastname: Almstrup
authors.forename: Anders
authors.initials: A
authors.lastname: Juul
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D008137:Longitudinal Studies; D007986:Luteinizing Hormone / Q000097:blood; D011446:Prospective Studies; D011627:Puberty / Q000097:blood*; D011629:Puberty, Precocious / Q000097:blood*; D012261:Ribonucleoproteins / Q000097:blood*; D044767:Ubiquitin-Protein Ligases
chemical_list: D012261:Ribonucleoproteins; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; C119425:MKRN3 protein, human; D044767:Ubiquitin-Protein Ligases