SRY – 46,XY Complete Gonadal Dysgenesis

SRY encodes the sex-determining region Y protein, the mammalian testis‐determining factor. Heterozygous mutations in its conserved HMG‐box domain abolish DNA binding and bending, leading to failure of testis differentiation and complete gonadal dysgenesis in 46,XY individuals (PMID:1415266).

Genetic evidence shows predominantly de novo, Y-linked heterozygous SRY variants in sporadic cases. A prototypic de novo point mutation c.337G>A (p.Ala113Thr) was first identified in a Chinese 46,XY female with streak gonads (PMID:8105086). Across decades, screening of >150 probands has revealed 45 distinct coding changes, including missense, nonsense, frameshift, and splice‐site mutations within the HMG box.

Segregation data include familial cases: two half‐sisters and a mosaic father carrying c.347T>C (p.Leu116Ser) (PMID:21868002), and three affected siblings in a non-consanguineous family with primary amenorrhea (PMID:29069951). Altogether, at least 5 additional affected relatives segregate pathogenic SRY alleles.

Functional studies of multiple HMG‐box mutants (e.g., p.Phe67Val, p.Trp70Ter) demonstrate graded reductions in DNA binding and bending, and impaired nuclear import via disrupted importin-β or calmodulin recognition (PMID:1339396; PMID:11641389). A frameshift c.244delA (p.Ser82AlafsTer) also yields truncated protein lacking DNA‐binding capacity (PMID:16106197).

Approximately 85% of 46,XY complete gonadal dysgenesis cases lack SRY coding mutations, implicating other downstream or regulatory genes in testis determination (PMID:1487248). Promoter deletions affecting Sp1 binding and deep‐intronic variants have also been reported.

Integration of genetic and functional data supports a mechanism of haploinsufficiency for SRY: loss of sequence‐specific DNA bending and nuclear localization disrupts SOX9 activation and Sertoli cell differentiation. Although additional regulators contribute to the 46,XY CGD phenotype, SRY mutation testing provides a definitive diagnosis in ~15% of cases.

Key Take-home: SRY HMG-box sequencing is clinically essential for diagnosing Swyer syndrome, guiding early gonadectomy and hormone replacement to prevent malignancy and promote normal pubertal development.

References

• American Journal of Human Genetics • 1992 • Evidence for increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis PMID:1415266
• Journal of Medical Genetics • 1993 • A new de novo mutation (A113T) in HMG box of the SRY gene leads to XY gonadal dysgenesis PMID:8105086
• Fertility and Sterility • 2011 • A novel missense mutation in the high mobility group domain of SRY drastically reduces its DNA-binding capacity and causes paternally transmitted 46,XY complete gonadal dysgenesis PMID:21868002
• Diagnostic Molecular Pathology • 2005 • A novel frame shift mutation in the HMG box of the SRY gene in a patient with complete 46,XY pure gonadal dysgenesis PMID:16106197
• Human Genetics • 1992 • Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal PMID:1339396
• Human Genetics • 1992 • Mutations in the conserved domain of SRY are uncommon in XY gonadal dysgenesis PMID:1487248

Evidence Based Scoring (AI generated)