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. 2017;105(1):17-25.
doi: 10.1159/000446963. Epub 2016 May 26.

High Frequency of MKRN3 Mutations in Male Central Precocious Puberty Previously Classified as Idiopathic

Danielle S Bessa  1 , Delanie B Macedo, Vinicius N Brito, Monica M França, Luciana R Montenegro, Marina Cunha-Silva, Leticia G Silveira, Tiago Hummel, Ignacio Bergadá, Debora Braslavsky, Ana Paula Abreu, Andrew Dauber, Berenice B Mendonca, Ursula B Kaiser, Ana Claudia Latronico
Affiliations

High Frequency of MKRN3 Mutations in Male Central Precocious Puberty Previously Classified as Idiopathic

Danielle S Bessa et al. Neuroendocrinology. 2017.

Abstract

Background/aims: Recently, loss-of-function mutations in the MKRN3 gene have been implicated in the etiology of familial central precocious puberty (CPP) in both sexes. We aimed to analyze the frequency of MKRN3 mutations in boys with CPP and to compare the clinical and hormonal features of boys with and without MKRN3 mutations.

Methods: This was a retrospective review of clinical, hormonal and genetic features of 20 male patients with idiopathic CPP evaluated at an academic medical center. The entire coding regions of MKRN3, KISS1 and KISS1R genes were sequenced.

Results: We studied 20 boys from 17 families with CPP. All of them had normal brain magnetic resonance imaging. Eight boys from 5 families harbored four distinct heterozygous MKRN3 mutations predicted to be deleterious for protein function, p.Ala162Glyfs*14, p.Arg213Glyfs*73, p.Arg328Cys and p.Arg365Ser. One boy carried a previously described KISS1-activating mutation (p.Pro74Ser). The frequency of MKRN3 mutations among these boys with idiopathic CPP was significantly higher than previously reported female data (40 vs. 6.4%, respectively, p < 0.001). Boys with MKRN3 mutations had typical clinical and hormonal features of CPP. Notably, they had later pubertal onset than boys without MKRN3 abnormalities (median age 8.2 vs. 7.0 years, respectively, p = 0.033).

Conclusion: We demonstrated a high frequency of MKRN3 mutations in boys with CPP, previously classified as idiopathic, suggesting the importance of genetic analysis in this group. The boys with CPP due to MKRN3 mutations had classical features of CPP, but with puberty initiation at a borderline age.

Keywords: Genetics; Gonadotropin-releasing hormone; MKRN3 gene; Male precocious puberty.

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Figures

Fig. 1
Fig. 1
Age at puberty onset in boys with idiopathic and genetic CPP. This information was not clear in 3 of 20 cases, which were excluded from the figure. The dashed line indicates the lower age limit for normal male puberty onset (9.0 years). The one boy with a KISS1 mutation started puberty at 1.0 year of age. The short horizontal lines indicate the median age at puberty onset (7.0 years in the boys with idiopathic CPP and 8.2 years in those with MKRN3 mutations). The boys with MKRN3 mutations had a significantly later pubertal onset compared to those with idiopathic CPP. p value as assessed with Mann-Whitney U test.
Fig. 2
Fig. 2
Schematic protein structure of MKRN3 and locations of loss-of-function mutations identified in patients with CPP. The three C3H zinc finger motifs are shown in yellow, the C3HC4 RING finger motif in orange, and the MKRN-specific Cys-His domain in green. The numbers correspond to the amino acid positions in the protein. Red arrows indicate the location of all described MKRN3 mutations in patients with CPP; black-red arrows indicate the mutations identified in boys with CPP.
See this image and copyright information in PMC

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