Genomic structure of HOXD13 gene: a nine polyalanine duplication causes synpolydactyly in two unrelated families

Synpolydactyly (SPD) is a limb malformation that shows a characteristicmanifestation in both hands and feet. This condition is inherited as anautosomal dominant trait with reduced penetrance. We have recently mappedthis locus centromeric to the HOXD8 intragenic marker and suggested theHOXD13 gene as a potential candidate for this condition. The genomicstructure of HOXD13 established in this study consists of two exons thatencodes a polypeptide of 335 amino acids. The downstream exon at the 3' endof this gene contains the homeodomain sequences that are highly conserved.Sixty-three bp upstream of this exon lies a stretch of intronic CA-repeatsthat proved to be polymorphic in two different populations. The upstreamexon encodes 75% of the entire protein and contains a stretch of 15 normalalanines at its 5' end. Sequence comparison at this position in thehomozygous affected individuals identified a total of 24 alanine residuesthat resulted from a duplication of nine polyalanines. In two unrelated SPDfamilies, this duplication was directly transmitted from the affectedparents to their affected, but not unaffected, offspring; in one family itssize has remained constant for at least 150 years spanning over sevengenerations. The presence of this duplication confirmed the status of fournormal gene carriers, one incomplete penetrance and two affectedindividuals who were recombinants for HOXD8 or HOXD13-CA repeat markers.This duplication was not present in 150 chromosomes of unrelated healthysubjects of two different populations.