Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation

Thompson, Alexis A.; Nguyen, Long

doi:10.1038/82511

Cited by 195 publications

(100 citation statements)

References 15 publications

(14 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Such perspectives provide insight into how the level of robustness of a system influences its response to mutation and is relevant to the establishment of genetic disease. In this regard, it is interesting to note that both human SHOX and human HOXA11 are considered haplo-insufficient loci (Rao et al 1997;Thompson and Nguyen 2000), suggesting the zeugopod genetic network they function in may be somewhat sensitive to mutation in general. While the sources of the dosage sensitivity in Hox-Shox networks are unknown, it may furthermore extend to Runx2 regulation, as disruption of a single Runx2 allele causes limb defects (Otto et al 1997).…”

Section: Discussionmentioning

confidence: 99%

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

2014

View full text Add to dashboard Cite

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 ...

show abstract

Section: Discussionmentioning

confidence: 99%

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

2014

View full text Add to dashboard Cite

show abstract

“…Single basepair deletions in HOXA11 cause amegakaryocytic thrombocytopenia and radioulnar synostosis. 40 Heterozygous mutations in HOXA13 are associated with handfoot -genital syndrome and the closely related Guttmacher syndrome. 41,42 A missense mutation in HOXD10 segregates in a family with rocker-bottom feet and Charcot-MarieTooth disease.…”

Section: Discussionmentioning

confidence: 99%

De novo t(12;17)(p13.3;q21.3) translocation with a breakpoint near the 5′ end of the HOXB gene cluster in a patient with developmental delay and skeletal malformations

Yue

Farcas

Thiel³

et al. 2007

Eur J Hum Genet

View full text Add to dashboard Cite

A boy with severe mental retardation, funnel chest, bell-shaped thorax, and hexadactyly of both feet was found to have a balanced de novo t(12;17)(p13.3;q21.3) translocation. FISH with BAC clones and longrange PCR products assessed in the human genome sequence localized the breakpoint on chromosome 17q21.3 to a 21-kb segment that lies o30 kb upstream of the HOXB gene cluster and immediately adjacent to the 3 0 end of the TTLL6 gene. The breakpoint on chromosome 12 occurred within telomeric hexamer repeats and, therefore, is not likely to affect gene function directly. We propose that juxtaposition of the HOXB cluster to a repetitive DNA domain and/or separation from required cis-regulatory elements gave rise to a position effect.

show abstract

“…Genetic analysis of two pedigrees identified one mutation in HoxA11, a member of a family of genes encoding for DNA-binding proteins involved in regulation of early hematopoiesis [28]. No consistent data are currently available about pathophysiology of ATRUS.…”

Section: Defective Mk Differentiationmentioning

confidence: 99%

Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists

Pecci

2013

Int J Hematol

View full text Add to dashboard Cite

Knowledge in the field of inherited thrombocytopenias (ITs) has considerably improved over the recent years. In the last 5 years, nine new genes whose mutations are responsible for thrombocytopenia have been identified, and this also led to the recognition of several novel nosographic entities, such as thrombocytopenias deriving from mutations in CYCS, TUBB1, FLNA, ITGA2B/ITGB3, ANKRD26 and ACTN1. The identification of novel molecular alterations causing thrombocytopenia together with improvement of methodologies to study megakaryopoiesis led to considerable advances in understanding pathophysiology of ITs, thus providing the background for proposing new treatments. Thrombopoietin-receptor agonists (TPO-RAs) represent an appealing therapeutic hypothesis for ITs and have been tested in a limited number of patients. In this review, we provide an updated description of pathogenetic mechanisms of thrombocytopenia in the different forms of ITs and recapitulate the current management of these disorders. Moreover, we report the available clinical and preclinical data about the role of TPO-RAs in ITs and discuss the rationale for the use of these molecules in view of pathogenesis of the different forms of thrombocytopenia of genetic origin.

show abstract

Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation

Cited by 195 publications

References 15 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

De novo t(12;17)(p13.3;q21.3) translocation with a breakpoint near the 5′ end of the HOXB gene cluster in a patient with developmental delay and skeletal malformations

Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists

Contact Info

Product

Resources

About