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A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome

✍ Scribed by Jeffrey W. Innis; Frances R. Goodman; Chiara Bacchelli; Thomas M. Williams; Douglas P. Mortlock; Praveen Sateesh; Peter J. Scambler; Wendy McKinnon; Alan E. Guttmacher

Publisher: John Wiley and Sons
Year: 2002
Tongue: English
Weight: 166 KB
Volume: 19
Category: Article
ISSN: 1059-7794
DOI: 10.1002/humu.9036

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✦ Synopsis

Communicated by Gregg Semenza

Guttmacher syndrome, a dominantly inherited combination of distal limb and genital tract abnormalities, has several features in common with hand-foot-genital syndrome (HFGS), including hypoplastic first digits and hypospadias. The presence of features not seen in HFGS, however, including postaxial polydactyly of the hands and uniphalangeal 2 nd toes with absent nails, suggests that it represents a distinct entity. HFGS is caused by mutations in the HOXA13 gene. We have therefore re-investigated the original Guttmacher syndrome family, and have found that affected individuals are heterozygous for a novel missense mutation in the HOXA13 homeobox (c.1112A>T; homeodomain residue Q50L), which arose on an allele already carrying a novel 2-bp deletion (-78-79delGC) in the gene's highly conserved promoter region. This deletion produces no detectable abnormalities on its own, but may contribute to the phenotype in the affected individuals. The missense mutation, which alters a key residue in the recognition helix of the homeodomain, is likely to perturb HOXA13's DNA-binding properties, resulting in both a loss and a specific gain of function.

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