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J Med Genet 40:e133 doi:10.1136/jmg.40.12.e133
  • Online mutation report

Rapp-Hodgkin and AEC syndromes due to a new frameshift mutation in the TP63 gene

  1. I Dianzani1,
  2. E Garelli2,
  3. P Gustavsson4,
  4. A Carando2,
  5. B Gustafsson3,
  6. N Dahl4,
  7. G Annerén4
  1. 1Department of Medical Sciences, Università del Piemonte Orientale, Novara, Italy
  2. 2Department of Pediatric Sciences, Università Torino, Italy
  3. 3Karolinska Institute, Stockholm, Sweden
  4. 4Department of Genetics and Pathology, Uppsala University, Sweden
  1. Correspondence to:
 Prof. I Dianzani
 Department of Medical Sciences, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy; irma.dianzanimed.unipmn.it
  • Received 1 January 2003
  • Accepted 21 May 2003

Increases in the number of allelic malformation syndromes (due to mutations in a single gene) have led to their classification according to their pathogenesis rather than their clinical specific phenotype. TP63 mutations have been identified in several such syndromes characterised by autosomal dominant transmission and various combinations of ectodermal dysplasia, limb malformations, and orofacial clefting.

The TP63 gene is a TP53 homologue,1–8 part of a family composed of only three members. The third member (TP73) is more similar to TP63 than to TP53 in both structure and function.9–13 Like p53, p63 has a transactivating (TA), a DNA binding (DB), and a polymerisation domain; it exerts p53-like activities in various contexts, such as binding canonical p53 sites, transactivating p53 target genes, and inducing apoptosis.1,2 Unlike TP53, which expresses one major transcript, TP63 contains four separate transcription initiation sites that direct expression of two fundamentally different isotypes that retain (TA products) or lack (ΔN products) the TA domain.14 Alternative splicing generates additional complexity at the C terminus.

ΔN isoforms lack TA activity and may also suppress the TA isoforms, either by simple competition for the DNA target sites or by acting as dominant negatives through oligomerisation. By contrast to p53, the C terminus in p63 is longer and contains a SAM domain and a TID (transactivation inhibitory domain). SAM domains are involved in protein-protein interactions and probably have regulatory functions in p63,15–17 since its TA-α isoform shows a lower TA activity than the γ form, which lacks the SAM but retains the TA domain. The TID has been mapped within the α tail downstream to the SAM domain.14 The differences at the C terminus identify three transcripts which have different properties and functions: α, β, and γ isoforms. The α isoforms have …