The Rapp–Hodgkin syndrome results from mutations of the TP63 gene

Bougeard, Gaëlle; Hadj‐Rabia, Smail; Faivre, Laurence; Sarafan-Vasseur, Nasrin; Frébourg, Thierry

doi:10.1038/sj.ejhg.5201004

Cited by 52 publications

(53 citation statements)

References 18 publications

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“…The Trp indole HN group are evidenced in Figure 4E with a dashed square and zoomed in Figure 4F. The left-most signal (10.08 1 H-ppm 128.7 15 N ppm) is in slow exchange and the corresponding bound species signal is increasing at 10.03 1 H-ppm and 129.8 15 N ppm (blue arrow), the resonance of the bound species is thus very close to the ones originating from the second Trp. The second Trp signal shows a fast exchange regime (black arrow) that is slightly shifting towards the resonance of the first Trp residue in its bound form.…”

Section: Resultsmentioning

confidence: 95%

“…[5][6][7][8] The p63 gene, the evolutionary progenitor and homolog of the TP53 gene, is responsible for several disorders known as ectodermal dysplasias. [9][10][11][12][13][14][15] p63 proteins have important functions in epithelial development and tumorigenesis as regulators of the proliferation potential of epithelial stem cells, as well as of cell death, reviewed in. [6][7][8][9][10][11][12][13][14][15][16][17][18] Thanks to two specific promoters, the TP63 gene is expressed as ΔNp63 and TAp63 proteins that have distinct functions in transcription control.…”

Section: Effect Of An Ectodermal Dysplasia Mutantmentioning

confidence: 99%

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Recognition of p63 by the E3 ligase ITCH: Effect of an ectodermal dysplasia mutant

Bellomaria¹,

Barbato²,

Melino³

et al. 2010

Cell Cycle

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Section: Resultsmentioning

confidence: 95%

Section: Effect Of An Ectodermal Dysplasia Mutantmentioning

confidence: 99%

Recognition of p63 by the E3 ligase ITCH: Effect of an ectodermal dysplasia mutant

Bellomaria¹,

Barbato²,

Melino³

et al. 2010

Cell Cycle

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“…While Itch is basically ubiquitous, the expression of the p53 family members, that is p63 and p73, [63][64][65][66][67][68] is strictly tissue-and cellspecific; moreover several disorders known as ectodermal dysplasias 12,[69][70][71][72][73][74][75] as well as cancer show a deregulated expression levels of p63 and p73. 39,76 Physiologically, p63 and p73 protein levels are normally kept under strict control through Itch-mediated ubiquitylation, and indeed both p63 and p73 have a canonical PY motif (absent in p53 which is regulated by a different E3 ligase) located in their C-terminal which accounts for the binding to Itch through its WW domains.…”

Section: -62mentioning

confidence: 99%

p63 threonine phosphorylation signals the interaction with the WW domain of the E3 ligase Itch

et al. 2014

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Both in epithelial development as well as in epithelial cancers, the p53 family member p63 plays a crucial role acting as a master transcriptional regulator. P63 steady state protein levels are regulated by the E3 ubiquitin ligase Itch, via a physical interaction between the PPxY consensus sequence (PY motif) of p63 and one of the 4 WW domains of Itch; this substrate recognition process leads to protein-ubiquitylation and p63 proteasomal degradation. The interaction of the WW domains, a highly compact protein-protein binding module, with the short proline-rich sequences is therefore a crucial regulatory event that may offer innovative potential therapeutic opportunity. Previous molecular studies on the Itch-p63 recognition have been performed in vitro using the Itch-WW2 domain and the peptide interacting fragment of p63 (pep63), which includes the PY motif. Itch-WW2-pep63 interaction is also stabilized in vitro by the conformational constriction of the S-S cyclization in the p63 peptide. The PY motif of p63, as also for other proteins, is characterized by the nearby presence of a (T/S)P motif, which is a potential recognition site of the WW domain of the IV group present in the prolyl-isomerase Pin1. In this study, we demonstrate, by in silico and spectroscopical studies using both the linear pep63 and its cyclic form, that the threonine phosphorylation of the (T/S)PPPxY motif may represent a crucial regulatory event of the Itch-mediated p63 ubiquitylation, increasing the Itch-WW domains-p63 recognition event and stabilizing in vivo the Itch-WW-p63 complex. Moreover, our studies confirm that the subsequently trans/cis proline isomerization of (T/S)P motif by the Pin1 prolyl-isomerase, could modulate the E3-ligase interaction, and that the (T/S) p P trans PPxY motif represent the best conformer for the ItchWW-(T/S)PPPxY motif recognition.

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“…A number of frameshift mutations in the TID of P63 have been previously described and result in either RH, limb-mammary or AEC syndrome. 10,18,30 The reason for this clinical variability is unclear and may be secondary to modifying alleles. 31 One of the previously reported mutations in RHS, c.1787delG, results in a mutant protein, which is very similar, except by one amino acid, to our cases.…”

Section: Wild-type Dlaslkipeqfrhaiwkgildhrqlhefsspshllrtpssastvsvgssementioning

confidence: 99%

“…2 Overlapping features with ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC or Hay -Wells syndrome, MIM 106260) and ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome (EEC, MIM 129900) have been previously reported. 3,4 Mutations of the TP63 gene have been identified in the following human malformation conditions: EEC syndrome, 5,6 AEC syndrome, 7 limb mammary syndrome (MIM 603543), 8 acrodermato-ungual-lacrimal-tooth syndrome (ADULT, MIM 103285), 9 nonsyndromic split-hand/foot malformation (MIM 183600), 10 isolated cleft lip/palate 11 and RHS. 12 Most of these entities are characterized by limb abnormalities that fit the split-hand/split-foot spectrum, ectodermal dysplasia affecting the hair, teeth, nails and sweat glands, and other malformations involving the face, the eyes and the urogenital system.…”

Section: Introductionmentioning

confidence: 99%

A new mutation in TP63 is associated with age-related pathology

et al. 2007

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Increases in the number of allelic malformation syndromes have led to their classification according to their pathogenesis rather than their clinical specific phenotype. TP63 (also known as TP73L) mutations have been identified in several such syndromes characterized by autosomal dominant transmission and various combinations of ectodermal dysplasia, limb malformations and orofacial clefting. TP63 has not yet been implicated in early aging phenotype in humans, even though p63 activates a program of cellular senescence and p63-compromised mice display features of accelerated aging. We report on a family with four affected adult females presenting with Rapp-Hodgkin syndrome (RHS), an autosomal dominant clinical entity that associates anhidrotic ectodermal dysplasia with cleft lip and palate. Features between RHS and EEC syndrome (ectrodactyly, ectodermal dysplasia and cleft lip/palate) have led to the recent identification of mutations in the TP63 gene, located on 3q27, in this condition. Our patients present typical clinical features of RHS, but also ophthalmic anomalies such as corneal dystrophy and premature menopause (around 30 years). The latter findings have never been reported in this condition, and could be secondary to a new TP63 deletion that has been identified in this family.

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The Rapp–Hodgkin syndrome results from mutations of the TP63 gene

Cited by 52 publications

References 18 publications

Recognition of p63 by the E3 ligase ITCH: Effect of an ectodermal dysplasia mutant

Recognition of p63 by the E3 ligase ITCH: Effect of an ectodermal dysplasia mutant

p63 threonine phosphorylation signals the interaction with the WW domain of the E3 ligase Itch

A new mutation in TP63 is associated with age-related pathology

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