SOX3 – X-linked Panhypopituitarism

SOX3, an X-linked transcription factor, is implicated in X-linked panhypopituitarism (MONDO:0010712) through rare point mutations and polyalanine tract alterations. Case reports and series provide moderate clinical validity based on familial segregation and supportive functional studies.

Clinical Validity

Multiple independent pedigrees demonstrate X-linked recessive inheritance of SOX3 variants in panhypopituitarism. A single family with three affected males segregating a hemizygous c.449C>A (p.Ser150Tyr) variant exhibited hypopituitarism and craniofacial anomalies, with maternal germline mosaicism confirmed by segregation analysis (PMID:29175558). Additional hemizygous point variants in two pedigrees further substantiate the association.

Genetic Evidence

Inheritance mode: X-linked recessive. Segregation: three affected male relatives in the index family (PMID:29175558). Case reports describe four probands across two pedigrees carrying distinct SOX3 missense variants (p.Ser150Tyr; p.Pro142Thr) with consistent endocrine phenotypes (PMID:30125608). Variant spectrum is limited to missense changes within the HMG-box and flanking regions; no recurrent or founder alleles have been reported.

Variant Spectrum

Reported variant: c.449C>A (p.Ser150Tyr). Missense point mutations cluster in the DNA-binding HMG domain and exhibit hemizygous loss-of-function effects. Polyalanine tract deletions and expansions are also observed in hypopituitarism but are outside the coding HMG-box region.

Functional Evidence

Polyalanine expansion mutations (22Ala, 26Ala) form cytoplasmic aggregates and aggresomes, disrupting nuclear localization and transactivation in vitro (PMID:17127446). Deletion of six alanines (p.Ala243_Ala248del) increases SOX3 transactivation of HESX1 in NT2/D1 cells, confirming dosage sensitivity in hypopituitarism (PMID:21289259). A novel p.Pro142Thr missense variant increases transcriptional activation and impairs β-catenin repression, linking altered Wnt signaling to pituitary dysfunction (PMID:30125608).

Integration and Conclusion

Collectively, genetic and in vitro evidence support a loss-of-function and dosage‐sensitive mechanism for SOX3 in X-linked panhypopituitarism. While case numbers remain limited, concordant segregation and multiple functional assays reach a Moderate strength of evidence by ClinGen criteria. Additional large‐scale studies may elevate this classification. Key take-home: Hemizygous SOX3 missense and polyalanine tract mutations cause X-linked panhypopituitarism, informing molecular diagnosis and genetic counseling.

References

• European journal of medical genetics • 2018 • A complex phenotype in a family with a pathogenic SOX3 missense variant. PMID:29175558
• Frontiers in bioscience : a journal and virtual library • 2007 • Polyalanine expansion mutations in the X-linked hypopituitarism gene SOX3 result in aggresome formation and impaired transactivation. PMID:17127446
• The Journal of clinical endocrinology and metabolism • 2011 • Increased transactivation associated with SOX3 polyalanine tract deletion in a patient with hypopituitarism. PMID:21289259
• Molecular and cellular endocrinology • 2018 • Increased transactivation and impaired repression of β-catenin-mediated transcription associated with a novel SOX3 missense mutation in an X-linked hypopituitarism pedigree with modest growth failure. PMID:30125608

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