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Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27. Am J Hum Genet 2000 Jul;67(1):59-66 PMID: 10839977 PMCID: PMC1287102

Pubmed ID

10839977

Abstract

Split-hand/split-foot malformation (SHFM), a limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals, is phenotypically analogous to the naturally occurring murine Dactylaplasia mutant (Dac). Results of recent studies have shown that, in heterozygous Dac embryos, the central segment of the apical ectodermal ridge (AER) degenerates, leaving the anterior and posterior segments intact; this finding suggests that localized failure of ridge maintenance activity is the fundamental developmental defect in Dac and, by inference, in SHFM. Results of gene-targeting studies have demonstrated that p63, a homologue of the cell-cycle regulator TP53, plays a critically important role in regulation of the formation and differentiation of the AER. Two missense mutations, 724A-->G, which predicts amino acid substitution K194E, and 982T-->C, which predicts amino acid substitution R280C, were identified in exons 5 and 7, respectively, of the p63 gene in two families with SHFM. Two additional mutations (279R-->H and 304R-->Q) were identified in families with EEC (ectrodactyly, ectodermal dysplasia, and facial cleft) syndrome. All four mutations are found in exons that fall within the DNA-binding domain of p63. The two amino acids mutated in the families with SHFM appear to be primarily involved in maintenance of the overall structure of the domain, in contrast to the p63 mutations responsible for EEC syndrome, which reside in amino acid residues that directly interact with the DNA.

Author List

Ianakiev P, Kilpatrick MW, Toudjarska I, Basel D, Beighton P, Tsipouras P

Author

Donald Basel MD Chief, Associate Professor in the Pediatrics department at Medical College of Wisconsin




Scopus

2-s2.0-0033926317   198 Citations

MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Base Sequence
Chromosomes, Human, Pair 3
DNA Mutational Analysis
DNA-Binding Proteins
Exons
Female
Foot Deformities, Congenital
Genes, Tumor Suppressor
Genetic Linkage
Hand Deformities, Congenital
Humans
Male
Membrane Proteins
Models, Molecular
Mutation
Pedigree
Phenotype
Phosphoproteins
Polymorphism, Single-Stranded Conformational
Protein Structure, Tertiary
Trans-Activators
Transcription Factors
Tumor Suppressor Proteins
jenkins-FCD Prod-296 4db9d02597e0a2e889e230f853b641c12f1c3ee3