Human Molecular Genetics, Vol 5, 945-952, Copyright © 1996 by Oxford University Press
AN Akarsu, I Stoilov, E Yilmaz, BS Sayli and M Sarfarazi
Synpolydactyly (SPD) is a limb malformation that shows a characteristic
manifestation in both hands and feet. This condition is inherited as an
autosomal dominant trait with reduced penetrance. We have recently mapped
this locus centromeric to the HOXD8 intragenic marker and suggested the
HOXD13 gene as a potential candidate for this condition. The genomic
structure of HOXD13 established in this study consists of two exons that
encodes a polypeptide of 335 amino acids. The downstream exon at the 3' end
of this gene contains the homeodomain sequences that are highly conserved.
Sixty-three bp upstream of this exon lies a stretch of intronic CA-repeats
that proved to be polymorphic in two different populations. The upstream
exon encodes 75% of the entire protein and contains a stretch of 15 normal
alanines at its 5' end. Sequence comparison at this position in the
homozygous affected individuals identified a total of 24 alanine residues
that resulted from a duplication of nine polyalanines. In two unrelated SPD
families, this duplication was directly transmitted from the affected
parents to their affected, but not unaffected, offspring; in one family its
size has remained constant for at least 150 years spanning over seven
generations. The presence of this duplication confirmed the status of four
normal gene carriers, one incomplete penetrance and two affected
individuals who were recombinants for HOXD8 or HOXD13-CA repeat markers.
This duplication was not present in 150 chromosomes of unrelated healthy
subjects of two different populations.
ARTICLES
Genomic structure of HOXD13 gene: a nine polyalanine duplication causes synpolydactyly in two unrelated families
Department of Surgery, University of Connecticut Health Center, Farmington, USA.
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