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?

• Published in: Human genetics 2002-05, Vol.110 (5), p.488-494
• Main Authors: UTSCH, Boris, BECKER, Karl, BROCK, Detlef, LENTZE, Michael J, BIDLINGMAIER, Frank, LUDWIG, Michael
• Format: Article
• Language: English
• Subjects: Alleles; Base Sequence; Biological and medical sciences; Complex syndromes; Exons - genetics; Female; Foot Deformities - genetics; Hand Deformities - genetics; Homeodomain Proteins - chemistry; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Male; Medical genetics; Medical sciences; Molecular Sequence Data; Mutation - genetics; Pedigree; Peptides - genetics; Repetitive Sequences, Nucleic Acid - genetics; Syndrome; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism; Urogenital Abnormalities - genetics
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-002-0712-8

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 homeoboxgene ( 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.