Genetic causes of central precocious puberty

Abstract

Central precocious puberty (CPP) is a condition in which the hypothalamus-pituitary-gonadal system is activated earlier than the normal developmental stage. The etiology includes organic lesions in the brain; however, in the case of idiopathic diseases, environmental and/or genetic factors are involved in the development of CPP. A genetic abnormality in KISS1R, that encodes the kisspeptin receptor, was first reported in 2008 as a cause of idiopathic CPP. Furthermore, genetic alterations in KISS1, MKRN3, DLK1, and PROKR2 have been reported in idiopathic and/or familial CPP. Of these, MKRN3 has the highest frequency of pathological variants associated with CPP worldwide; but, abnormalities in MKRN3 are rare in patients in East Asia, including Japan. MKRN3 and DLK1 are maternal imprinting genes; thus, CPP develops when a pathological variant is inherited from the father. The mechanism of CPP due to defects in MKRN3 and DLK1 has not been completely clarified, but it is suggested that both may negatively control the progression of puberty. CPP due to such a single gene abnormality is extremely rare, but it is important to understand the mechanisms of puberty and reproduction. A further development in the genetics of CPP is expected in the future.

Keywords: DLK1; MKRN3; genetic factor; precocious puberty.

Fig. 1.

Schema of KNDy and GnRH neurons. (A) The ARC comprises KNDy neurons that contain kisspeptin, neurokinin B, and dynorphin A. Kisspeptin is released from the KNDy neurons and stimulates GnRH release from GnRH neurons. Neurokinin B plays a dual role as a stimulator of kisspeptin release; and with a short delay, expression of dynorphin A upregulates, and the activity and release of kisspeptin decreases. MKRN3 is also expressed in the kisspeptin-expressing neurons. It remains uncertain whether MKRN3 is expressed in the GnRH neurons. (B) An in vitro study showed that MKRN3 represses KISS1 and TAC3 encoding neurokinin B promoter activity, suppressing the GnRH release. (C) MBD3 is known to bind gene promoters, exons, and enhancers, and actively regulates DNA transcription. In GnRH neurons, MKRN3 interacts with and ubiquinates MBD3. Ubiquitination of MBD3 promotes DNA methylation of the GnRH promoter and suppresses GnRH transcription. MKRN3 also ubiquitinates PABPs, destabilizing GnRH mRNA and decreasing transcription of GnRH. MBD, methyl-CpG-binding domain; PABPs, poly(A)-binding proteins.

Fig. 2.

The structure of MKRN3 and known variants. MKRN3 is a zinc-finger protein comprising 507 amino acids. MKRN3 has a unique composition of several C3H zinc-finger motifs, including a motif that is rich in Cys and His residues. C3H zinc-finger domains are characteristic of ribonucleoproteins and function in RNA-binding. A RING zinc-finger domain is found in E3 ubiquitin ligase enzymes that mediates the transfer of ubiquitin from E2 ubiquitin-conjugating enzymes to target proteins. Frameshift and nonsense variants are shown above the MKRN3 structure. Missense variants are shown below the MKRN3 structure. In Japan, only p.Glu229Argfs*3 has been reported (shaded). Six variants in the 5’-upstream region have also been reported.

Fig. 3.

The structure of DLK1 and reported variants. DLK1 contains 383 amino acids and consists of an extracellular region with six epidermal growth factor-like repeats, a transmembrane domain, and a short intracellular tail. Six abnormalities in DLK1 have also been reported.

Fig. 4.

The schema of DLK1 function in the MBH. (A) DLK1 is expressed in the cell membrane of kisspeptin-expressing neurons. DLK1 interacts with NOTCH1 receptor and competes with binding by canonical-activating NOTCH ligands, blocking the NOTCH signaling. (B) It is hypothesized that defects in DLK1 excessively activate NOTCH signaling; the enhanced signaling causes abnormal cell proliferation and/or differentiation of kisspeptin neurons and the development of CPP. NICD, Notch intracellular domain.