Human Genetics

, Volume 110, Issue 5, pp 488–494

A novel stable polyalanine [poly(A)] expansion in the HOXA13 gene associated with hand-foot-genital syndrome: proper function of poly(A)-harbouring transcription factors depends on a critical repeat length?

Authors

  • Boris Utsch
    • Children's Hospital Medical Center, University of Bonn, Adenauerallee 119, 53113 Bonn, Germany
  • Karl Becker
    • Johanniter Children's Hospital, Dept. Pediatric Surgery, Arnold-Janssen-Str. 29, 53757 St. Augustin, Germany
  • Detlef Brock
    • Johanniter Children's Hospital, Dept. Pediatric Surgery, Arnold-Janssen-Str. 29, 53757 St. Augustin, Germany
  • Michael J. Lentze
    • Children's Hospital Medical Center, University of Bonn, Adenauerallee 119, 53113 Bonn, Germany
  • Frank Bidlingmaier
    • Dept. of Clinical Biochemistry, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany
  • Michael Ludwig
    • Dept. of Clinical Biochemistry, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany
Original Investigation

DOI: 10.1007/s00439-002-0712-8

Cite this article as:
Utsch, B., Becker, K., Brock, D. et al. Hum Genet (2002) 110: 488. doi:10.1007/s00439-002-0712-8

Abstract.

Hand-foot-genital syndrome (HFGS) is a dominantly inherited congenital malformation affecting the distal limbs and genitourinary tract. Here, we describe the phenotype and its molecular basis in a family that presented with HFGS. Genetic analysis revealed that the condition is caused by an 18-bp in-frame duplication within a cryptic trinucleotide repeat sequence encoding an 18-residue polyalanine tract in the homeobox gene (HOX) A13. This mutation expands the stretch with six extra alanine residues. Similar types of mutation (plus eight alanines) have recently been found in another HFGS family and also in the human HOXD13 gene (plus seven up to plus 14 residues) where it leads to synpolydactyly (SPD), a further congenital limb malformation rarely associated with genital abnormalities. As observed in our family, all the expanded tracts encoding polyalanine, either reported for HOXA13 or HOXD13, are quite stable when transmitted within affected families. Unlike disorders with unstable expansions of perfect trinucleotide repeats the molecular mechanism underlying these polyalanine expansions should be unequal crossing-over rather than replication slippage. The alanine tract elongation may prevent protein-protein interactions of the mutant HOXA13, thereby inducing a localized heterochrony in the sequence of distal limb and genitourinary development.

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Copyright information

© Springer-Verlag 2002