Mutation of HOXA13 in hand-foot-genital syndrome

Abstract

There are several human syndromes which involve defects of the limbs and the Müllerian ducts or its derivatives. The hand-foot-genital (HFG) syndrome is an autosomal dominant, fully penetrant disorder that was originally described by Stern et al. Additional reports describing other affected families have also been published. Limb anomalies include short first metacarpals of normal thickness, small distal phalanges of the thumbs, short middle phalanges of the fifth fingers, and fusion or delayed ossification of wrist bones. In the feet, the great toe is shorter due to a short first metatarsal and a small, pointed distal phalanx. Uterine anomalies are common in females with HFG, and typically involve a partially divided (bicornuate) or completely divided (didelphic) uterus, representing defects of Müllerian duct fusion. Urinary tract malformations in affected HFG females include a displaced urethral opening and malposition of ureteral orifices in the bladder wall; affected males may have hypospadias (ventrally misplaced urethral opening) of variable severity. We report the identification of a HOXA13 nonsense mutation in a family with hand-foot-genital syndrome. The mutation converts a highly conserved tryptophan residue in the homeodomain to a stop codon, which truncates 20 amino acids from the protein and likely eliminates or greatly reduces the ability of the protein to bind to DNA.

A new approach to the treatment of congenital vertical talus

“…HOX genes are a large group of highly conserved transcription factors that control development along the body axis. Mutations in several of the HOX genes have been shown to result in a variety of both upper and lower extremity abnormalities including synpolydactyly [21], radioulnar synostosis and amegakaryocytic thrombocytopenia [22], and hand-foot-genital syndrome [23].…”

Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome

“…The mechanisms that regulate early development of the genital tubercle are not well understood. Several genes, including Shh (Haraguchi et al, 2001), Fgf (Haraguchi et al, 2000), and Hox genes (Mortlock and Innis, 1997), have been implicated in the control of genital outgrowth. Loss of Wnt5a leads also to impaired distal outgrowth of limbs and the genital tubercle (Yamaguchi et al, 1999).…”

Hox Proteins Functionally Cooperate with the GC Box-binding Protein System through Distinct Domains

“…One of the helix 3 mutants, A13-dC33, is similar to the human Hoxa-13 mutant, which causes hand-foot-genital syndrome. Hand-foot-genital syndrome is a dominantly inherited condition affecting the distal limbs and genitourinary tract (57). The associated phenotypes are more severe in hand-foot-genital syndrome than in targeted disruption or deletion of mouse Hoxa-13 (58).…”