Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Mutation of HOXA13 in hand-foot-genital syndrome


There are several human syndromes which involve defects of the limbs and the Müllerian ducts or its derivatives1–3. The hand-foot-genital (HFG) syndrome is an autosomal dominant, fully penetrant disorder that was originally described by Stern et al.4 Additional reports describing other affected families have also been published1,5–11. 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 severity1,5,7–9. 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others


  1. Verp, M.S. et al. Heritable aspects of uterine anomalies. I. Three familial aggregates with Müllerian fusion anomalies. Fert Steril. 40, 80–65 (1983).

    Article  CAS  Google Scholar 

  2. Pinsky, L. A community of human malformation syndromes involving the Müllerian ducts, distal extremities, urinary tract, and ears. Teratol. 9, 65–80 (1973).

    Article  Google Scholar 

  3. Halal, F. A new syndrome of severe upper limb hypoplasia and Müllerian duct anomalies. Am.J.Med.Genet. 24, 119–126 (1986).

    Article  CAS  Google Scholar 

  4. Stern, A.M. et al. The hand-foot-uterus syndrome. J.Pediat 77, 109–116 (1970).

    Article  CAS  Google Scholar 

  5. Giedion, A. & Prader, A. Hand-foot-uterus (HFU) syndrome with hypospadias: the hand-foot-genital (HFG) syndrome. Pediat.Radiol. 4, 96–102 (1976).

    Article  CAS  Google Scholar 

  6. Halal, F., Hand-Foot-Genital (Hand-Foot-Uterus) Syndrome: family report and update. Am.J.Med.Genet. 30, 793–803 (1988).

    Article  CAS  Google Scholar 

  7. Donnenfeld, A.E., Schrager, D.S. & Corson, S.L. Update on a family with Hand-foot-genital syndrome: hypospadias and urinary tract abnormalities in two boys from the fourth generation. Am.J.Med.Genet. 44, 482–484 (1992).

    Article  CAS  Google Scholar 

  8. Fryns, J.P., Vogels, A., Decock, P. & van den Berghe, H. . The hand-foot-genital syndrome: on the variable expression in affected males. Clinical Genet. 43, 232–234 (1993).

    Article  CAS  Google Scholar 

  9. Verp, M.S. Urinary tract abnormalities in Hand-foot-genital syndrome. Am. J. Med. Genet. 32, 555 (1989).

    Article  CAS  Google Scholar 

  10. Poznanski, A.K., Stern, A.S. & Gall, J.C. Radiographic findings in the Hand-Foot-Uterus Syndrome (HFUS). Radiol. 95, 129–134 (1970).

    Article  CAS  Google Scholar 

  11. Cleveland, R.H. & Holmes, L.B. Hand-foot-genital syndrome: the importance of hallux varus. Pediat.Radiol. 20, 339–343 (1990).

    Article  CAS  Google Scholar 

  12. Mortlock, D.P., Post, L.C. & Innis, J.W. The molecular basis of hypodactyly (Hd): a deletion in Hoxa13 leads to arrest of digital arch formation. Nature Genet 13, 284–289 (1996).

    Article  CAS  Google Scholar 

  13. Hummel, K., Hypodactyly, a semidominant lethal mutation in mice. J.Hered. 61, 219–220 (1970).

    Article  CAS  Google Scholar 

  14. Borrow, J. et al. The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9. Nature Genet 12, 159–167 (1996).

    Article  CAS  Google Scholar 

  15. Gyapay, G. et al. The 1993-94 Genethon human genetic linkage map. Nature Genet 7, 246–339 (1994).

    Article  CAS  Google Scholar 

  16. Duboule, D. Guidebook to the Homeobox Genes (Oxford University Press, New York, 1994).

  17. Muragaki, Y., Mundlos, S., Upton, J. & Olsen, B.R. Altered growth and branching patterns in synpolydactyly caused by mutations in HOXD13. Science 272, 548–551 (1996).

    Article  CAS  Google Scholar 

  18. Copeland, J.W.R., Nasiadka, A., Dietrich, B. & Krause, H. Patterning of the Drosophila embryo by a homeodomain-deleted Ftz polypeptide. Nature 379, 162–165 (1996).

    Article  CAS  Google Scholar 

  19. Schnabel, C. & Abate-Shen, C. Repression by HoxA7 is mediated by the homeodomain and the modulatory action of its N-terminal-arm residues. Mol.Cell.Biol. 16, 2678–2688 (1996).

    Article  CAS  Google Scholar 

  20. Vershon, A., Jin, Y. & Johnson, A. A homeo domain protein lacking specific side chains of helix 3 can still bind DNA and direct transcriptional repression. Genes.Dev. 9, 182–192 (1995).

    Article  CAS  Google Scholar 

  21. Zappavigna, V., Sartori, D. & Mavilio, F. Specificity of HOX protein function depends on DNA-protein and protein-protein interactions, both mediated by the homeo domain. Genes.Dev. 8, 732–744 (1994).

    Article  CAS  Google Scholar 

  22. Acién, P. Embryological observations on the female genital tract. Human Reprod. 7, 437–445 (1992).

    Article  Google Scholar 

  23. Blüm, V. Vertebrate Reproduction (Springer-Verlag, Berlin/Heidelberg, 1986).

  24. Gruenwald, P. The relation of the growing Müllerian duct to the Wolffian duct and its importance for the genesis of malformations. Anat.Rec. 81, 1–19 (1941).

    Article  Google Scholar 

  25. Sharman, G.B. Reproductive physiology of marsupials. Science 167, 1221–1228 (1970).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations


Rights and permissions

Reprints and permissions

About this article

Cite this article

Mortlock, D., Innis, J. Mutation of HOXA13 in hand-foot-genital syndrome . Nat Genet 15, 179–180 (1997).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing