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Idiopathic central precocious puberty (ICPP) is defined by the premature activation of the hypothalamic–pituitary–gonadal axis in the absence of organic lesions. The imprinted gene MKRN3 is paternally expressed and encodes makorin ring finger protein 3, a critical inhibitor of pubertal initiation. Loss-of-function variants in MKRN3 have been repeatedly identified in patients with ICPP, establishing a direct genetic etiology for this disorder.
Genetic studies have revealed 18 distinct loss-of-function and 5 missense MKRN3 variants in 71 patients from 36 unrelated families, all following autosomal dominant inheritance with paternal expressionPMID:33383582. The spectrum includes frameshift, nonsense, and missense mutations. A recurrent variant, c.203G>A (p.Arg68His), was identified in a sporadic case and multiple familial ICPP cases, confirming pathogenicity by in silico prediction and absence in control populationsPMID:27931036.
Segregation analysis across these families demonstrated perfect co-segregation of paternally inherited MKRN3 alleles with early-onset puberty, with affected relatives in each pedigree carrying the same variant. Penetrance is high when the variant is inherited from the father, consistent with imprinting, and no disease manifests when the maternal allele is mutated.
Functional assays support a loss-of-function mechanism: MKRN3 variants impair autoubiquitination and protein degradation, diminish suppression of GNRH1 transcription, and fail to repress human KISS1 and TAC3 promoter activity in vitroPMID:32407292. In mice, hypothalamic Mkrn3 mRNA levels are high in prepubertal animals and decline immediately before puberty, mirroring human disease onset and defining MKRN3 as a gatekeeper of pubertal timingPMID:23738509.
No conflicting evidence disputing the MKRN3–ICPP association has been reported. Comprehensive clinical and functional data over a decade support a definitive gene–disease relationship, with imprinting effects fully explaining inheritance patterns and variable expressivity.
Integration of genetic and experimental findings confirms that MKRN3 loss-of-function variants disrupt the ubiquitin-mediated repression of GnRH-related signaling, precipitating premature activation of the reproductive axis. Given the high diagnostic yield and therapeutic implications, targeted MKRN3 testing is recommended for patients with familial or early-onset ICPP.
Key Take-home: MKRN3 mutations cause a definitive form of idiopathic central precocious puberty, and genetic screening of MKRN3 should be incorporated into the diagnostic workup of early-onset pubertal disorders.
Gene–Disease AssociationDefinitive71 probands across 36 unrelated families with paternally inherited MKRN3 variants and consistent functional evidence Genetic EvidenceStrong18 loss-of-function and 5 missense variants in 71 patients (36 families) with perfect segregation of paternal allelesPMID:33383582 Functional EvidenceStrongIn vitro ubiquitination and promoter-reporter assays demonstrate loss-of-function; mouse Mkrn3 expression decline aligns with pubertal timingPMID:23738509, PMID:32407292 |