title: Pathogenesis of split-hand/split-foot malformation.
abstract: Split-hand/split-foot malformation (SHFM), also known as ectrodactyly, is a congenital limb malformation, characterized by a deep median cleft of the hand and/or foot due to the absence of the central rays. SHFM may occur as an isolated entity or as part of a syndrome. Both forms are frequently found in association with chromosomal rearrangements such as deletions or translocations. Detailed studies of a number of mouse models for ectrodactyly have revealed that a failure to maintain median apical ectodermal ridge (AER) signalling is the main pathogenic mechanism. A number of factors complicate the identification of the genetic defects underlying human ectrodactyly: the limited number of families linked to each SHFM locus, the large number of morphogens involved in limb development, the complex interactions between these morphogens, the involvement of modifier genes, and the presumed involvement of multiple genes or long-range regulatory elements in some cases of ectrodactyly. So far, the only mutations known to underlie SHFM in humans have been found in the TP63 gene. The identification of novel human and mouse mutations for ectrodactyly will enhance our understanding of AER functions and the pathogenesis of ectrodactyly.
authors.affiliation: Department of Human Genetics 417, University Medical Centre Nijmegen, Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Pascal H G
authors.initials: PH
authors.lastname: Duijf
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D002874:Chromosome Mapping; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005532:Foot Deformities, Congenital / Q000235:genetics* / Q000473:pathology; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D006228:Hand Deformities, Congenital / Q000235:genetics* / Q000473:pathology; D053823:Hedgehog Proteins; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008953:Models, Anatomic; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics; D015398:Signal Transduction; D013577:Syndrome; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins
chemical_list: C081876:CKAP4 protein, human; D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D011973:Receptors, LDL; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse; D025521:Tumor Suppressor Proteins; D002784:Cholesterol