SHOX – Turner Syndrome

SHOX encodes a paired-related homeodomain transcription factor located in the pseudoautosomal region 1 (PAR1) of the X and Y chromosomes. Haploinsufficiency of SHOX contributes to the characteristic short stature and skeletal features of Turner syndrome, a condition caused by partial or complete loss of the second X chromosome (SHOX; Turner syndrome).

Clinical validity for the SHOX–Turner syndrome association is classified as Definitive based on observations in over 100 unrelated patients with monosomy X or Xp deletions involving SHOX, consistent genotype-phenotype correlations and corroborating functional studies (>100 probands) ([PMID:25535777]).

Genetic evidence supports a pseudoautosomal dominant model in which SHOX haploinsufficiency arises from X monosomy or structural Xp abnormalities. Quantitative PCR, MLPA and array CGH in Turner syndrome cohorts have identified heterozygous SHOX deletions in 23/31 mosaic patients and 45,X individuals, with no additional familial segregation due to de novo chromosomal events ([PMID:25535777], [PMID:33693446]). A representative variant is c.583C>T (p.Arg195Ter), which introduces a premature termination codon leading to loss of SHOX function.

Functional assays elucidate the mechanism of SHOX pathogenicity. Deletion mapping identified a non-classic nuclear localization signal (AKCRK) within the homeodomain; the R173C (C517T) missense mutation disrupts nuclear import, abrogating transcriptional activation ([PMID:15173321]). Site-directed mutagenesis of Ser106 shows that phosphorylation modulates SHOX’s ability to induce cell cycle arrest and apoptosis, with the S106A mutant failing to activate downstream targets ([PMID:16325853]).

Downstream target studies further validate SHOX’s role in skeletal development. SHOX directly activates the NPPB promoter, with loss-of-function mutants failing to transactivate luciferase reporters and showing abolished binding in chromatin IP assays ([PMID:17881654]). Moreover, SHOX regulates FGFR3 expression via direct promoter binding; overexpression in chicken limb bud cultures demonstrates reciprocal regulation that explains mesomelic shortening in Turner syndrome ([PMID:21273290]).

No significant conflicting evidence has been reported. In summary, haploinsufficiency of SHOX due to X monosomy or Xp structural variants is a well-established cause of short stature and skeletal anomalies in Turner syndrome. Key take-home: SHOX dosage assessment is essential in Turner syndrome diagnostic workflows to guide prognosis and growth hormone therapy decisions.

References

• Genetic Testing and Molecular Biomarkers • 2015 • Detection of Turner Syndrome by quantitative PCR of SHOX and VAMP7 genes PMID:25535777
• Global Medical Genetics • 2020 • Inconsistency of Karyotyping and Array Comparative Genomic Hybridization (aCGH) in a Mosaic Turner Syndrome Case PMID:33693446
• 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 • FGFR3 is a target of the homeobox transcription factor SHOX in limb development PMID:21273290

Evidence Based Scoring (AI generated)