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HOXD13 and Synpolydactyly 

HOXD13 and Synpolydactyly
Chapter:
HOXD13 and Synpolydactyly
Author(s):

Frances R. Goodman

and Peter J. Scambler

DOI:
10.1093/med/9780199934522.003.0093
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date: 07 March 2021

HOXD13 (homeobox D13), the most 5 member of the HOXD gene cluster, encodes a highly conserved transcription factor that plays a crucial role in the development of the autopod; but the molecular pathway in which it acts is poorly understood. Little is known about how its expression is regulated, and none of its target genes or transcriptional cofactors has yet been identified. Synpolydactyly (SPD), the first human birth defect found to be caused by mutations in a HOX gene, is a rare, dominantly inherited malformation of the hands and feet, characterized by soft tissue syndactyly between the third and fourth fingers and between the fourth and fifth toes, with variable digit duplication in the syndactylous web. Most cases result from different-sized expansions of a polyalanine tract in HOXD13’s N-terminal region, and both penetrance and phenotypic severity have been shown to correlate positively with expansion size. The mutant protein appears to interfere functionally with both the remaining wild-type HOXD13 and other 5′ HOXD proteins expressed in the developing autopod, acting as a “super” dominant-negative protein. A milder atypical form of SPD, characterized by a distinctive foot phenotype, results from a variety of other HOXD13 mutations, all of which are likely to cause functional haploinsufficiency. In addition, two unusual forms of brachydactyly, distinct from SPD but exhibiting overlap with brachydactyly types D and E, result from specific missense mutations in the HOXD13 homeodomain, which alter rather than abolish DNA binding. The abnormalities in these conditions appear to reflect disturbances of patterning and growth both at the early stage of autopod development in undifferentiated mesenchyme and at a later stage in the chondrogenic cells of cartilaginous bone models. These observations suggest that downstream targets of HOXD13 are likely to include genes with important roles in cell sorting/boundary formation and cell cycle control.

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