Goodman, Frances Rebecca; (2000) Human malformations caused by mutations in the 5' Hox genes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The Hox genes are fundamental regulators of embryonic development in virtually all multicellular organisms. Here I describe a number of human malformations due to mutations in two of these genes, HOXD13 and HOXA13. The dominantly-inherited limb malformation synpolydactyly (SPD) is caused by expansions of an N-terminal polyalanine tract in HOXD13. Analysis of 20 affected families shows a highly significant increase in penetrance and phenotypic severity with increasing expansion size. In a family with a 14-residue expansion, the longest so far reported, affected individuals have an unusually severe limb phenotype; affected males also have hypospadias, not previously described in SPD. The expansions appear to confer a progressive gain of function on the mutant protein, perhaps by perturbing interactions with another protein. A novel phenotype, similar to but distinct from classical SPD, co-segregates with deletions in HOXD13 in two further families. These deletions truncate the first exon and the homeobox respectively, probably resulting in non-functional proteins. A virtually identical phenotype occurs in a father and daughter hemizygous for a microdeletion encompassing HOXD8 to HOXD13 and EVX2. These patients' phenotype nevertheless differs strikingly from that in Hoxdl3 knock-out mice. In another family, a novel polydactyly/brachydactyly syndrome including distal ulnar abnormalities co-segregates with an amino acid substitution in the homeodomain of HOXD13. Here, altered DNA-binding capacity appears to affect protein function in a way different to either the gain-of-function or the loss-of-function mutations described above. The dominantly-inherited hand-foot-genital syndrome (HFGS) has been shown in one family to be caused by a nonsense mutation in HOXA13. In three further HFGS families, I have identified three novel HOXA13 mutations: a premature stop, a polyalanine tract expansion, and an amino-acid substitution in the homeodomain. Intriguingly, the associated phenotype is subtly different in each family, suggesting that each mutation exerts a distinctive effect.

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