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Kallmann syndrome (KS) is defined by congenital hypogonadotropic hypogonadism with anosmia, reflecting disrupted development or migration of gonadotropin-releasing hormone neurons. DUSP6 encodes dual-specificity phosphatase 6 (MKP-3), a negative regulator of ERK1/2 within FGF8-FGFR1 signaling pathways critical for GnRH neuron differentiation.
In a cohort of 386 unrelated congenital hypogonadotropic hypogonadism (CHH) patients, heterozygous DUSP6 missense variants were identified in 5 probands ([PMID:23643382]). A large Chinese isolated hypogonadotropic hypogonadism (IHH) series (n = 196) revealed 4 heterozygous DUSP6 variants in six patients ([PMID:32389901]). Exome sequencing of 158 normosmic HH/KS patients detected one P/LP DUSP6 c.566A>G (p.Asn189Ser) variant in a single individual ([PMID:38593951]). Overall, DUSP6 variants have been reported in 11 unrelated KS/IHH probands.
Segregation analyses demonstrate that DUSP6 variants are often inherited from unaffected parents, indicating incomplete penetrance and an oligogenic or modifier role rather than a straightforward Mendelian mechanism. In one Tunisian KS patient, a DUSP6 variant co-occurred with a novel SEMA7A VUS in a digenic context, absent in the healthy parent, consistent with dual molecular diagnosis ([PMID:34539727]). No definitive co-segregation of DUSP6 variants with disease in multiple affected relatives has been documented.
Functionally, DUSP6 dephosphorylates ERK1/2 to fine-tune FGF8-FGFR1 signaling during GnRH neuron development. Despite clear mechanistic rationale, direct assays linking patient-derived DUSP6 variants to altered phosphatase activity or GnRH neuron deficits in KS are lacking. No rescue or in vivo disease models have been reported for these specific variants.
No studies have formally refuted the involvement of DUSP6 in KS, but the lack of segregation and consistent monoallelic pathogenicity weakens its role as a primary KS gene. Instead, evidence supports DUSP6 as a genetic contributor within an oligogenic architecture of KS.
In conclusion, heterozygous DUSP6 missense variants have been observed in a limited number of KS/IHH probands, predominantly within oligogenic combinations without clear segregation. This supports a contributory modifier role of DUSP6 in KS rather than a standalone causal gene. Additional familial segregation and functional validation are needed to elevate the clinical validity. Key take-home: DUSP6 variants may predispose to Kallmann syndrome in an oligogenic autosomal dominant context but currently exhibit limited clinical validity.
Gene–Disease AssociationLimited11 probands with heterozygous DUSP6 variants in KS/IHH across multiple cohorts, no segregation, oligogenic context Genetic EvidenceLimitedTotal 11 unrelated probands with DUSP6 variants ([PMID:23643382],[PMID:32389901],[PMID:38593951]); inheritance from unaffected parents indicates modifier role Functional EvidenceLimitedDUSP6 is a known ERK phosphatase within FGF8-FGFR1 signaling but lacks direct variant-specific functional assays or disease models in KS |