Makorin RING finger protein 3 and central precocious puberty

Abstract

Makorin RING finger protein 3 (MKRN3) is a key inhibitor of the hypothalamic-pituitary-gonadal axis. Loss-of-function mutations in MKRN3 cause familial and sporadic central precocious puberty (CPP), while polymorphisms are associated with age at menarche. To date, 115 patients with CPP carrying MKRN3 mutations have been described, harboring 48 different genetic variants. The prevalence of MKRN3 mutations in genetically screened populations with CPP is estimated at 9.0%. Girls are more commonly and more seriously affected than boys. MKRN3 is expressed in humans and rodents in the central nervous system. Circulating levels in humans and hypothalamic expression in rodents decrease during pubertal progression. Although some MKRN3 regulators have been identified, the precise mechanism by which MKRN3 inhibits the hypothalamic-pituitary-gonadal axis remains elusive. The role of makorins in developmental physiology and organ differentiation and the role of maternal imprinting are discussed herein.

Keywords: Development; Estradiol; GnRH; Imprinting; Kisspeptin; Makorin; Puberty.

Figure 1. Schematic depiction of the makorin RING finger protein 3 (MKRN3) structure and location of mutations reported in patients with central precocious puberty.

Protein structure: numbers indicate amino acids from 1 to 507. The canonical zinc fingers (C3H) typical of RNA binding activity are depicted in blue, the makorin-type Cys–His (CH)–rich hinge region is depicted in green, and the RING finger domain (C3HC4) characteristic of E3 ubiquitin ligase activity is depicted in red. The locations of mutations in MKRN3 identified in patients with central precocious puberty that result in amino acid substitutions are indicated by green arrows (missense variants) and those resulting in protein truncation or frameshift mutations are indicated by purple arrows (nonsense variants). The insets show two-dimensional details of the different MKRN3 domains.

Figure 2. Schematic depiction of hypothalamic regions involved in MKRN3 action.

This figure summarizes the predominant sites of expression of MKRN3 within the hypothalamus. Putative regions and nuclei are encircled by dotted blue lines. The GnRH neuron is depicted in purple. Kisspeptin and KNDy neurons are shown in blue. Other putative MKRN3-expressing neurons are shown in gray. The inset shows the intracellular site of action of MKRN3 and the currently proposed mechanisms of action and regulation. The red X indicates inhibitory action. ARC, arcuate nucleus; AVPV, anteroventral periventricular nucleus; DMH, dorsomedial hypothalamic nucleus; ME, median eminence; MnPO, median preoptic nucleus; POA, preoptic area; VMN, ventromedial nucleus.

Figure 3. Pedigree showing a family with the M268Vfs*23 MKRN3 mutation associated with central precocious puberty (CPP).

Squares indicate males, circles indicate females, black symbols indicate CPP-affected members, and symbols with a black dot inside indicate asymptomatic carriers. Symbols with a star inside indicate DNA sample unavailability. The arrow indicates the proband. Reprinted from the study by Simsek et al. [21] with permission. Please note that only individuals inheriting the mutation from the father are affected. By contrast, those inheriting the mutation from their mother are unaffected carriers.