SOX3 – Panhypopituitarism

SOX3 encodes an SRY-related HMG-box transcription factor on the X chromosome. Hemizygous variants in SOX3 cause X-linked recessive panhypopituitarism, characterized by combined anterior pituitary hormone deficiencies and structural pituitary anomalies. Female carriers may be asymptomatic or show variable hypopituitarism. Diagnosis relies on molecular testing for SOX3 deletions, polyalanine tract variants, and rare missense mutations.

Genetic evidence includes a Japanese Kabuki syndrome patient with a novel hemizygous 21-bp deletion removing seven alanines from the first polyalanine tract of SOX3, associated with combined pituitary hormone deficiency and increased HESX1 promoter activity in vitro (PMID:24346842). A subsequent screening of 154 patients with undescended posterior pituitary identified an 18-bp deletion c.726_743del (p.Ala243_Ala248del) in a female patient with hypopituitarism and two male siblings with isolated GH deficiency, confirming familial segregation in two affected relatives (PMID:21289259).

Further support arises from a Chinese pedigree harboring a rare SOX3 missense variant c.424C>A (p.Pro142Thr) showing increased transactivation and impaired β-catenin repression in vitro, consistent with partial gain-of-function contributing to variable hypopituitarism phenotypes (PMID:30125608). Large CPHD cohorts reveal SOX3 alterations in <2% of cases, underscoring rarity but specificity of the phenotype (PMID:20534763).

Functional assays across multiple studies demonstrate that SOX3 polyalanine tract expansions and deletions cause protein misfolding, cytoplasmic aggregation, and altered transcriptional activity. Expanded tracts (+7A or +11A) form aggresomes and impair transactivation, while deletions enhance HESX1 promoter activation, providing a coherent mechanism of dosage-sensitive dysregulation in pituitary development (PMID:17127446).

No convincing conflicting evidence has been reported; rare SOX3 missense variants outside functional domains remain of uncertain significance. Overall, the clinical validity meets a Moderate level under ClinGen criteria given replication across multiple families, segregation data, and concordant functional studies.

Key Take-home: SOX3 molecular testing is recommended in male patients with panhypopituitarism or CPHD presenting with anterior pituitary hypoplasia or ectopic posterior pituitary, as detection of PA tract variants or missense mutations informs diagnosis, genetic counselling, and early hormone replacement therapy.

References

• Pituitary | 2014 | A novel mutation in SOX3 polyalanine tract: a case of Kabuki syndrome with combined pituitary hormone deficiency harboring double mutations in MLL2 and SOX3. PMID:24346842
• 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
• 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 | 2010 | Mutation and gene copy number analyses of six pituitary transcription factor genes in 71 patients with combined pituitary hormone deficiency: identification of a single patient with LHX4 deletion. PMID:20534763

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