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Heterozygous variants in DUSP6 have been reported in patients with congenital hypogonadotropic hypogonadism (CHH), indicating an autosomal dominant inheritance pattern. In a sequencing study of 386 unrelated CHH individuals, five probands carried missense DUSP6 mutations, including c.566A>G (p.Asn189Ser) (PMID:23643382). A separate cohort of 196 Chinese patients identified four heterozygous DUSP6 variants in six affected individuals, without segregation to unaffected relatives (PMID:32389901). In total, 11 unrelated probands have been reported with DUSP6 variants, but no additional affected family members have been documented.
DUSP6 encodes the dual-specificity phosphatase MKP-3, a critical negative regulator of FGFR1–ERK signaling in GnRH neuron development. In vitro assays and interactome-based affiliation scoring support a role for DUSP6 loss in elevated ERK activity and defective GnRH secretion. Phosphorylation studies in cellular models demonstrate ERK1/2-mediated feedback on MKP-3 stability, underscoring mechanism relevance (PMID:15632084). Despite functional concordance, the paucity of segregation data and absence of CHH-specific animal models limit the evidence. Key take-home: DUSP6 variants likely contribute to CHH pathogenesis through ERK signaling dysregulation but require further familial and in vivo confirmation for diagnostic use.
Gene–Disease AssociationLimited11 probands across two cohorts; no segregation data; oligogenic modifiers noted Genetic EvidenceLimited11 unrelated CHH patients with heterozygous DUSP6 variants; lacking familial segregation Functional EvidenceModerateIn vitro and interactome analyses demonstrate DUSP6-ERK pathway dysregulation; feedback phosphorylation validated |