MAP3K1 – 46,XY Complete Gonadal Dysgenesis

46,XY complete gonadal dysgenesis (Swyer syndrome) is characterized by a 46,XY karyotype with female external genitalia, streak gonads, hypergonadotropic hypogonadism and primary amenorrhea. This disorder follows an autosomal dominant inheritance pattern when caused by heterozygous gain-of-function variants in the mitogen-activated protein kinase kinase kinase 1 gene MAP3K1. Clinical presentation often includes absence of functional testicular tissue, elevated gonadotropins (HP:0000815) and primary amenorrhea (HP:0000786).

Genetic evidence for the association is robust. To date, four unrelated probands have been reported with heterozygous MAP3K1 missense variants: c.570G>C (p.Lys190Asn) in exon 2 ([PMID:36088066]), c.2117T>G (p.Leu706Arg) ([PMID:31446095]), c.556A>G (p.Arg186Gly) ([PMID:35309143]) and c.3020A>G (p.Gln1007Arg) ([PMID:36102299]). Additionally, a maternally inherited c.2254C>T variant yields altered splicing (p.Gln752_Arg790del) segregating with gonadal dysgenesis in two affected siblings ([PMID:33060765]). These six affected individuals across five families establish autosomal dominant inheritance with 2 segregations.

Segregation analysis in the family carrying c.2254C>T demonstrates cosegregation in two siblings with undermasculinized genitalia and partial androgen insensitivity, fulfilling criteria for pathogenicity ([PMID:33060765]). This multi-family recurrence and segregation data support a strong genetic contribution.

Functional studies across multiple models concordantly show MAP3K1 gain-of-function as the pathogenic mechanism. Missense mutations cluster in three non-kinase domains and increase binding to RHOA and MAP3K4, augmenting phosphorylation of downstream targets ERK1/2, p38 and MAPK11 ([PMID:30608580]). These alterations shift signaling from SOX9/FGF9 toward WNT/β-catenin/FOXL2, consistent with testicular failure ([PMID:24135036]).

In vivo and in vitro assays further confirm that aberrant MAP3K1 activity disrupts co-factor interactions (e.g., RAC1), enhances β-catenin nuclear localization and downregulates SOX9 and SRY expression, culminating in complete gonadal dysgenesis.

Together, genetic and experimental data fulfill ClinGen criteria for a Strong gene-disease association with Strong genetic evidence and Moderate functional evidence. MAP3K1 sequencing should be integrated into diagnostic panels for 46,XY DSD, guiding early diagnosis, genetic counseling and management.

Key Take-home: Heterozygous gain-of-function MAP3K1 variants cause autosomal dominant 46,XY complete gonadal dysgenesis through dysregulated MAP kinase and β-catenin signaling, warranting routine inclusion in DSD genetic testing.

References

• Taiwanese journal of obstetrics & gynecology • 2022 • Novel mutation of MAP3K1 gene in 46,XY DSD with complete gonadal dysgenesis. PMID:36088066
• Gene • 2019 • Novel pathogenic mutations in disorders of sex development associated genes cause 46,XY complete gonadal dysgenesis. PMID:31446095
• Frontiers in genetics • 2022 • MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY Disorders/Differences of Sex Development PMID:35309143
• Molecular medicine reports • 2022 • Identification of a novel MAP3K1 variant in a family with 46, XY DSD and partial growth hormone deficiency. PMID:36102299
• Scientific reports • 2020 • Nonsense-associated altered splicing of MAP3K1 in two siblings with 46,XY disorders of sex development. PMID:33060765
• Human molecular genetics • 2019 • Mutations in MAP3K1 that cause 46,XY disorders of sex development disrupt distinct structural domains in the protein. PMID:30608580
• Human molecular genetics • 2014 • Mutations in MAP3K1 tilt the balance from SOX9/FGF9 to WNT/β-catenin signaling PMID:24135036

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