Bougeard Gaëlle, Hadj-Rabia Smaïl, Faivre Laurence, Sarafan-Vasseur Nasrin, Frébourg Thierry
INSERM EMI 9906-IFRMP, Faculty of Medicine and Pharmacy, 22 Boulevard Gambetta, 76183 Rouen, France.
Eur J Hum Genet. 2003 Sep;11(9):700-4. doi: 10.1038/sj.ejhg.5201004.
The Rapp-Hodgkin syndrome (RHS, MIM 129400) corresponds to a rare form of anhydrotic ectodermal dysplasia, which shares some features with the ectrodactyly, ectodermal dysplasia and cleft lip/palate syndrome (EEC, MIM 604292) resulting from TP63 mutations. We report here, in two unrelated patients with RHS, the identification of two distinct TP63 mutations, corresponding to a novel frameshift mutation (1709DelA, exon 14) located downstream the sterile alpha motif (SAM) domain and to a missense mutation (R279H, exon 7) within the DNA binding domain. Functional analysis of the R279H mutation, which had previously been reported in several EEC families, shows that this mutation disrupted the dominant negative activity of the DeltaNp63alpha and gamma isoforms on the transcriptional activity of TP53. This report shows, on a molecular basis, that RHS is also an EEC-like syndrome resulting from mutations of the TP63 gene, and highlights the wide phenotypic spectrum associated to TP63 mutations.
拉普-霍奇金综合征（RHS，MIM 129400）是无汗性外胚层发育不良的一种罕见形式，它与由TP63基因突变导致的缺指（趾）、外胚层发育不良和唇腭裂综合征（EEC，MIM 604292）有一些共同特征。我们在此报告，在两名无关的RHS患者中，鉴定出两种不同的TP63突变，一种是位于无菌α基序（SAM）结构域下游的新型移码突变（1709DelA，外显子14），另一种是位于DNA结合结构域内的错义突变（R279H，外显子7）。对R279H突变的功能分析（该突变先前已在多个EEC家族中报道）表明，此突变破坏了DeltaNp63α和γ亚型对TP53转录活性的显性负性作用。本报告从分子层面表明，RHS也是一种由TP63基因突变导致的类似EEC的综合征，并突出了与TP63突变相关的广泛表型谱。
