SHOX – SHOX-related Short Stature

SHOX haploinsufficiency underlies a spectrum of growth defects ranging from Léri-Weill dyschondrosteosis to isolated SHOX-related short stature. A novel 15.5 kb intragenic deletion encompassing exons 3–6 was identified in a three-generation family, segregating with variable short stature phenotypes and demonstrating an Alu-mediated recombination mechanism (PMID:27994182). Additional case reports describe intronic and splice-site mutations—such as c.-432-3C>A impacting splice acceptor fidelity in intron 1 (PMID:23426818) and the pseudo-autosomal recessive c.544+5G>C variant causing leaky intron retention (PMID:37107635)—all leading to SHOX deficiency and short stature.

Segregation analysis across multiple families confirms pseudo-autosomal dominant inheritance with at least nine affected relatives showing co-segregation of heterozygous SHOX variants. Population studies and the SHOX allelic variant database catalog 199 intragenic mutations—126 unique—and emphasize recurrent deletions and point mutations in coding and flanking enhancer regions (PMID:17726696). The spectrum includes missense (e.g., c.698C>T (p.Ala233Val)), nonsense, frameshift, deep-intronic, and 5′UTR alterations (e.g., c.-9del), collectively supporting robust genetic evidence.

Functional studies delineate a clear loss-of-function mechanism. Disruption of the nuclear localization signal via R173C (c.517C>T (p.Arg173Cys)) abrogates nuclear import and transcriptional activity (PMID:15173321). Phosphorylation at Ser106 modulates SHOX stability and transcriptional activation; S106A mutants fail to induce cell-cycle arrest and apoptosis in osteogenic cells (PMID:16325853). SHOX directly transactivates key growth-plate targets, including NPPB and the aggrecan enhancer via SOX5/SOX6 interactions; mutants disrupting these interactions impair reporter activation and chondrogenesis (PMID:17881654; PMID:21262861).

Rescue experiments and animal morpholino knockdowns further affirm that SHOX dosage dictates limb growth, with combined depletion of SHOX and modifiers (e.g., CYP26C1) exacerbating mesomelic shortening. No conflicting associations have been reported for SHOX-related short stature.

Together, extensive genetic case series, segregation data, and convergent functional assays establish a definitive gene-disease relationship. SHOX genetic testing, including deletion/duplication and point mutation analysis, is recommended for individuals presenting with idiopathic short stature or mesomelic limb shortening.

Key Take-home: SHOX haploinsufficiency is a definitive cause of SHOX-related short stature, with clear implications for diagnosis, genetic counseling, and tailored orthopedic management.

References

• Journal of genetics • 2016 • Identification of a novel 15.5 kb SHOX deletion associated with marked intrafamilial phenotypic variability and analysis of its molecular origin. PMID:27994182
• Journal of pediatric endocrinology & metabolism • 2012 • A novel intronic mutation in SHOX causes short stature by disrupting a splice acceptor site: direct demonstration of aberrant splicing by expression of a minigene in HEK-293T cells. PMID:23426818
• Genes • 2023 • Leri-Weill Dyschondrosteosis Caused by a Leaky Homozygous SHOX Splice-Site Variant. PMID:37107635
• Journal of cell science • 2004 • Impairment of SHOX nuclear localization as a cause for Léri-Weill syndrome PMID:15173321
• Journal of molecular biology • 2006 • Phosphorylation on Ser106 modulates the cellular functions of the SHOX homeodomain protein. PMID:16325853
• Human molecular genetics • 2007 • BNP is a transcriptional target of the short stature homeobox gene SHOX. PMID:17881654
• Human molecular genetics • 2011 • SHOX interacts with the chondrogenic transcription factors SOX5 and SOX6 to activate the aggrecan enhancer. PMID:21262861

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