The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome

Clement-Jones, Mark; Schiller, Simone; Rao, Ercole; Blaschke, R.; Zúñiga, Aimée; Zeller, Rolf; Robson, Stephen C.; Binder, Gerhard; Glass, Ian A.; Strachan, Tom; Lindsay, Susan; Rappold, Gudrun

doi:10.1093/hmg/9.5.695

Cited by 375 publications

(241 citation statements)

References 34 publications

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“…It has indeed been previously shown that a human SHOX knock-in allele is able to compensate for the loss of mouse Shox2 in the developing forelimb (Liu et al 2011). Interestingly, the reported SHOX2 expression domains in chicks and humans are restricted to the stylopod (Clement-Jones et al 2000;Tiecke et al 2006), suggesting that the distally extended expression of mouse Shox2 may be a derived feature in rodents. And second, although the individual mutation of mouse Shox2 has little effect on the newborn zeugopod, its mutation in sensitized Hox backgrounds demonstrates its prominent function in this region.…”

Section: Discussionmentioning

confidence: 86%

Genetic Interactions Between Shox2 and Hox Genes During the Regional Growth and Development of the Mouse Limb

2014

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The growth and development of the vertebrate limb relies on homeobox genes of the Hox and Shox families, with their independent mutation often giving dose-dependent effects. Here we investigate whether Shox2 and Hox genes function together during mouse limb development by modulating their relative dosage and examining the limb for nonadditive effects on growth. Using double mRNA fluorescence in situ hybridization (FISH) in single embryos, we first show that Shox2 and Hox genes have associated spatial expression dynamics, with Shox2 expression restricted to the proximal limb along with Hoxd9 and Hoxa11 expression, juxtaposing the distal expression of Hoxa13 and Hoxd13. By generating mice with all possible dosage combinations of mutant Shox2 alleles and HoxA/D cluster deletions, we then show that their coordinated proximal limb expression is critical to generate normally proportioned limb segments. These epistatic interactions tune limb length, where Shox2 underexpression enhances, and Shox2 overexpression suppresses, Hox-mutant phenotypes. Disruption of either Shox2 or Hox genes leads to a similar reduction in Runx2 expression in the developing humerus, suggesting their concerted action drives cartilage maturation during normal development. While we furthermore provide evidence that Hox gene function influences Shox2 expression, this regulation is limited in extent and is unlikely on its own to be a major explanation for their genetic interaction. Given the similar effect of human SHOX mutations on regional limb growth, Shox and Hox genes may generally function as genetic interaction partners during the growth and development of the proximal vertebrate limb.T HE vertebrate limb is a valuable model for studying the genetic coordination of a complex developing structure. The proximodistal axis of the limb is composed of discrete segments, the growth and development of which are selectively perturbed when individual, or combinations of, homeobox genes are disrupted. In mice, mutations of the paralogous Hox9 and Hox10 genes result in shortened stylopodal elements (containing the humerus and femur) (FromentalRamain et al. 1996a;Wellik and Capecchi 2003), deletions of Hox11 genes result in truncated zeugopodal elements (radius/ ulna and fibula/tibia) (Davis et al. 1995;Wellik and Capecchi 2003), and disruption of Hox13 genes results in agenesis of the autopod (metacarpals/metatarsals and the digits) (FromentalRamain et al. 1996b). Mutation of short stature homeobox (Shox) genes similarly gives rise to the disproportionate shortening of certain limb regions. In humans, loss of SHOX leads to the truncated zeugopod elements found in people with LeriWeill, Turner, and Langer syndromes (Rao et al. 1997;Belin et al. 1998;Shears et al. 1998;Zinn et al. 2002). While rodents have uniquely lost the Shox gene among mammals (Gianfrancesco et al. 2001), disruption of the widely conserved Shox2 gene results in severely shortened stylopodal elements in mice (Cobb et al. 2006). Thus, Hox and Shox gene perturbations each give ...

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Section: Discussionmentioning

confidence: 86%

Genetic Interactions Between Shox2 and Hox Genes During the Regional Growth and Development of the Mouse Limb

2014

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“…SHOX is a clinically important protein as its homozygous loss results in Langer mesomelic dysplasia while its haploinsufficiency has been shown to cause Léri-Weill dyschondrosteosis and is found in 2-3% of patients with idiopathic short stature. Additionally it has also been implicated in Turner syndrome (Rao et al, 1997;Belin et al, 1998;Shears et al, 1998;Clement-Jones et al, 2000;Schiller et al, 2000;Rappold et al, 2002;Binder et. al., 2003).…”

Section: Discussionmentioning

confidence: 99%

“…The heterozygous loss of SHOX function by deletions or other mutations has been shown to cause Léri-Weill dyschondrosteosis while its homozygous loss results in Langer mesomelic dysplasia (Rao et al, 1997;Belin et al, 1998;Shears et al, 1998). In addition, SHOX haploinsufficiency has also been demonstrated in patients with idiopathic short stature and Turner syndrome (Clement-Jones et al, 2000;Schiller et al, 2000;Rappold et al, 2002). Impairment of the SHOX nuclear translocation caused by mutations within its NLS is expected to interfere with its inherent function and therefore may provide a molecular explanation for the phenotype, e.g.…”

Section: Introductionmentioning

confidence: 99%

Impairment of SHOX nuclear localization as a cause for Léri-Weill syndrome

Sabherwal

Schneider

Blaschke

et al. 2004

Journal of Cell Science

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We report the characterization of the nuclear localization signal (NLS) of the short stature homeobox gene SHOX. Mutations within the SHOX gene cause Léri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LD) as well as idiopathic short stature (ISS). Furthermore, haploinsufficiency of SHOX has also been implicated in Turner syndrome. SHOX has been shown to be a cell-type-specific transcriptional activator that localizes to the nucleus. The SHOX protein contains a central homeodomain that together with its transactivation domain regulates the transcription of its target sequences within the nucleus. The sequences for its nuclear localization have not been identified yet. Experimental characterization of SHOX-NLS by deletion mapping identified a non-classic type basic signal, AKCRK, in the recognition helix of the homeodomain. Fusion of this stretch of five amino acids to a cytoplasmic reporter protein resulted in its nuclear translocation. Functional analysis of a missense mutation R173C (C517T) affecting the identified SHOX-NLS in two families with LWS and LD showed that the mutated SHOX protein is unable to enter the nucleus. Conversely, we can demonstrate that insertion of the identified signal adjacent to the mutant site can restore its nuclear translocation. These results establish impairment of nuclear localization as a mechanistic basis for SHOX-related diseases.

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“…A zooblot analysis of SHOX and SHOX2 revealed an absence of both genes in all the invertebrates studied but their presence in all vertebrates studied suggests that these two genes have a central role in the development of the internal skeleton and its related structures (Clement-Jones et al, 2000). An SHOX ortholog does not exist in mice, but the true mouse Shox2 ortholog has been identified (Rovescalli et al, 1996;Clement-Jones et al, 2000). The mouse Shox2 shares 99% identity at the amino acid level with its human counterpart (Blaschke et al, 1998;Semina et al, 1998).…”

Section: Introductionmentioning

confidence: 97%

“…They share 83% homology at the amino acid level and have an identical homeodomain. The expression of SHOX2 has been detected in the limb bud, branchial arches, nasal processes, heart, central nervous system and genital tubercle of human embryos (Clement-Jones et al, 2000). However, SHOX2 has not yet been linked to any known syndromes so far.…”

Section: Introductionmentioning

confidence: 99%

Shox2-deficient mice exhibit a rare type of incomplete clefting of the secondary palate

et al. 2005

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The short stature homeobox gene SHOX is associated with idiopathic short stature in humans, as seen in Turner syndrome and Leri-Weill dyschondrosteosis, while little is known about its close relative SHOX2. We report the restricted expression of Shox2 in the anterior domain of the secondary palate in mice and humans. Shox2-/- mice develop an incomplete cleft that is confined to the anterior region of the palate, an extremely rare type of clefting in humans. The Shox2-/- palatal shelves initiate, grow and elevate normally, but the anterior region fails to contact and fuse at the midline, owing to altered cell proliferation and apoptosis, leading to incomplete clefting within the presumptive hard palate. Accompanied with these cellular alterations is an ectopic expression of Fgf10 and Fgfr2c in the anterior palatal mesenchyme of the mutants. Tissue recombination and bead implantation experiments revealed that signals from the anterior palatal epithelium are responsible for the restricted mesenchymal Shox2 expression. BMP activity is necessary but not sufficient for the induction of palatal Shox2 expression. Our results demonstrate an intrinsic requirement for Shox2 in palatogenesis, and support the idea that palatogenesis is differentially regulated along the anteroposterior axis. Furthermore, our results demonstrate that fusion of the posterior palate can occur independently of fusion in the anterior palate.

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The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome

Cited by 375 publications

References 34 publications

Genetic Interactions Between Shox2 and Hox Genes During the Regional Growth and Development of the Mouse Limb

Genetic Interactions Between Shox2 and Hox Genes During the Regional Growth and Development of the Mouse Limb

Impairment of SHOX nuclear localization as a cause for Léri-Weill syndrome

Shox2-deficient mice exhibit a rare type of incomplete clefting of the secondary palate

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