HOXA13 Hand-Foot-Genital Syndrome and Guttmacher Syndrome
- DOI:
- 10.1093/med/9780199934522.003.0091
HOX gene mutations in humans associated with specific morphological defects have been described for 8 of the 39 HOX genes, HOXA1, HOXA2, HOXA11, HOXA13, HOXB1, HOXC13, HOXD10, and HOXD13. Except for HOXA1, HOXA2, HOXB1 and HOXC13, in which abnormalities occur with homozygous mutations, all of these human syndromes are associated with heterozygous HOX mutations that are inherited in an autosomal dominant pattern with complete penetrance. For HOXA13, heterozygous premature chain termination, missense and polyalanine expansion mutations cause distal limb and genitourinary malformations in humans. Haploinsufficiency for HOXA13 in humans causes Hand-foot-genital syndrome (HFGS), which is characterized by symmetric preaxial deficiency of the hands and feet, second and fifth finger clinodactyly, and frequent but incompletely penetrant genitourinary defects including incomplete Müllerian fusion in females and hypospadias in males. In-frame polyalanine expansions in any one of three, long polyalanine tracts also result in typical HFGS features. However, missense mutations in the HOXA13 homeodomain may act dominantly to cause either a more severe HFGS-like phenotype or the Guttmacher syndrome of preaxial deficiency, postaxial polydactyly, and hypospadias. Mouse models of Hoxa13 deficiency have similar malformations and are valuable tools for understanding the cellular consequences of HOX mutations in humans.
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