ESPE Yearbook of Paediatric Endocrinology

Brief summary: This article shows that intra-cerebroventricular injections of a recombinant adeno-associated virus expressing MKRN3 resulted in delayed puberty in female mice.

MKRN3 loss-of-function mutation is the most frequent cause of familial central precocious puberty (CPP) (1).

These authors investigated the effect of MKRN3 overexpression on pubertal timing, by generating a mouse model of neonatal hypothalamic Mkrn3 overexpression. Furthermore, they collected tissues from the mediobasal hypothalamus (MBH) to measure expression of genes encoding kisspeptin, neurokinin B, dynorphin, which are other known regulators of pubertal initiation (2). Arcuate nucleus neurokinin B and kisspeptin protein levels were assessed in order to explore the potential mechanisms of action of Mkrn3.

Overexpression of Mkrn3 in female mice resulted in delayed vaginal opening and first estrus, compared with controls, but with subsequent normal fertility. Interestingly, there was no change in pubertal timing in male mice, using preputial separation as the marker of pubertal onset. This sexual dimorphism in the effect of MKRN3 deletion has also been observed in humans (3).

Mkrn3 overexpression resulted in reduced hypothalamic kisspeptin and neurokinin B protein levels, but increased Kiss1, Tac2, and Pdyn mRNA levels in the MBH in females at postnatal day 28. These data suggests that MKRN3 may be involved in protein degradation of the KNDy neuron neuropeptides, thereby resulting in a compensatory increase in their mRNA levels. The exact mechanism of this interaction requires further study.

In conclusion, the authors demonstrated that hypothalamic overexpression of Mkrn3 delays pubertal onset in female mice, by a potential interaction between MKRN3 and Kiss1 neurons. MKRN3 gain of function could therefore be a candidate explanation for delayed puberty.

References: 1. Valadares LP, Meireles CG, De Toledo IP, Santarem de Oliveira R, Gonçalves de Castro LC, Abreu AP, Carroll RS, Latronico AC, Kaiser UB, Guerra ENS, Lofrano-Porto A. MKRN3 mutations in central precocious puberty: a systematic review and meta-analysis. J Endocr Soc. 2019; 3(5):979–995. 2. Perry JR, Day F, Elks CE, et al. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature. 2014; 514(7520):92–97. 3. Seraphim CE, Canton APM, Montenegro L, et al. Genotype-phenotype correlations in central precocious puberty caused by MKRN3 mutations. J Clin Endocrinol Metab. 2021;106(4):1041–1050.