MKRN3 – Central Precocious Puberty

MKRN3, encoding makorin RING-finger protein 3, is a paternally expressed imprinted gene located at chromosome 15q11-q13. Loss-of-function mutations in MKRN3 lead to premature activation of the hypothalamic–pituitary–gonadal axis, manifesting as central precocious puberty (CPP). The imprinted pattern ensures that only paternally inherited alleles are expressed, with pathogenic variants causing CPP only when transmitted from the father.

Clinical genetic evidence supports a definitive association: MKRN3 mutations have been identified in >100 unrelated probands with CPP, including 89 mutation-positive subjects (76 girls) across 22 studies ([PMID:31041429]) and segregate perfectly with paternal inheritance in >15 multigenerational families ([PMID:23738509]). Variants comprise heterozygous frameshift, nonsense, and missense changes, as well as promoter and 5ʹ-UTR alterations, consistent with loss-of-function.

Case reports and series describe 89 probands with diverse pathogenic MKRN3 variants, including the recurrent missense change c.1018T>G (p.Cys340Gly) in familial CPP ([PMID:24438377]). Variant classes span 20+ unique alleles: frameshift (e.g., c.441del (p.His148ThrfsTer23)), nonsense (e.g., c.841C>T (p.Gln281Ter)), and multiple missense substitutions clustering in the C3HC4 RING-finger domain.

Functional studies demonstrate that MKRN3 acts as an E3 ubiquitin ligase repressing GnRH1, KISS1, and TAC3 promoter activity. Mutations within the RING domain reduce ubiquitination and impair inhibition of GnRH1 transcription in vitro ([PMID:32407292]), and novel variants (e.g., c.980G>A (p.Arg327His)) attenuate MKRN3 autoubiquitination and degradation ([PMID:38054352]). Rodent hypothalamic expression shows high prepubertal Mkrn3 levels that decline at puberty, corroborating a repressive role ([PMID:23738509]).

No credible conflicting evidence has been reported. The consistency of genetic segregation, diverse variant spectrum, and concordant functional data across multiple populations establish MKRN3 deficiency as a definitive cause of CPP.

Key Take-home: Paternally inherited MKRN3 loss-of-function mutations represent a definitive monogenic etiology for central precocious puberty, informing genetic counseling, early diagnosis, and targeted endocrine management.

References

• The New England journal of medicine • 2013 • Central precocious puberty caused by mutations in the imprinted gene MKRN3. PMID:23738509
• Journal of the Endocrine Society • 2019 • MKRN3 Mutations in Central Precocious Puberty: A Systematic Review and Meta-Analysis. PMID:31041429
• The Journal of Clinical Investigation • 2020 • MKRN3 inhibits the reproductive axis through actions in kisspeptin-expressing neurons. PMID:32407292
• American Journal of Medical Genetics. Part A • 2024 • The functional study of a novel MKRN3 missense mutation associated with familial central precocious puberty. PMID:38054352

Evidence Based Scoring (AI generated)