Rapp–Hodgkin syndrome and SHFM1 patients: Delineating the p63–Dlx5/Dlx6 pathway

Vera-Carbonell, Ascensión; Moya‐Quiles, María Rosa; Ballesta-Martínez, Maria Juliana; López‐González, Vanesa; Bafalliu, Juan Antonio; Guillén-Navarro, Encarna; López-Expósito, Isabel

doi:10.1016/j.gene.2012.01.088

Cited by 15 publications

(13 citation statements)

References 38 publications

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“…In mice, for instance, synergistic regulatory interactions between dlx5 and other transcription factors have been found to be essential for the formation of the frontal bone 76 . Other studies also showed that dlx5 is involved in morphogenesis of different facial structures formed by soft tissues in vertebrates 77,80,81 . The potential role of dlx5a in development and morphogenesis of non-skeletal craniofacial tissues in fish has not been investigated so far.…”

Section: Discussionmentioning

confidence: 90%

Molecular mechanisms underlying nuchal hump formation in dolphin cichlid, Cyrtocara moorii

Lecaudey

Sturmbauer

Singh

et al. 2019

Sci Rep

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East African cichlid fishes represent a model to tackle adaptive changes and their connection to rapid speciation and ecological distinction. In comparison to bony craniofacial tissues, adaptive morphogenesis of soft tissues has been rarely addressed, particularly at the molecular level. The nuchal hump in cichlids fishes is one such soft-tissue and exaggerated trait that is hypothesized to play an innovative role in the adaptive radiation of cichlids fishes. It has also evolved in parallel across lakes in East Africa and Central America. Using gene expression profiling, we identified and validated a set of genes involved in nuchal hump formation in the Lake Malawi dolphin cichlid, Cyrtocara moorii. In particular, we found genes differentially expressed in the nuchal hump, which are involved in controlling cell proliferation (btg3, fosl1a and pdgfrb), cell growth (dlk1), craniofacial morphogenesis (dlx5a, mycn and tcf12), as well as regulators of growth-related signals (dpt, pappa and socs2). This is the first study to identify the set of genes associated with nuchal hump formation in cichlids. Given that the hump is a trait that evolved repeatedly in several African and American cichlid lineages, it would be interesting to see if the molecular pathways and genes triggering hump formation follow a common genetic track or if the trait evolved in parallel, with distinct mechanisms, in other cichlid adaptive radiations and even in other teleost fishes.

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Section: Discussionmentioning

confidence: 90%

Molecular mechanisms underlying nuchal hump formation in dolphin cichlid, Cyrtocara moorii

Lecaudey

Sturmbauer

Singh

et al. 2019

Sci Rep

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“…In the recessive form SHFM type-VI, the WNT10b gene has recently been found mutated (15). The existence of several phenocopies of ectrodactyly has long suggested the possibility that the corresponding disease genes might participate in a regulatory cascade; however, the only established link is the transcriptional regulation of p63 on Dlx5;Dlx6 (7,25,50). By examining the murine models of SHFM available to date, namely the p63 null , p63 EEC (for SHFM-IV and EEC), the Dlx5;Dlx6 DKO (for SHFM-I) and the spontaneous mutant strain Dactylaplasia ( Dac , for SHFM-III), the striking observation is that in all these models the AER shows reduced FGF8 expression and lack or has impaired stratification, with accompanying limb developmental defects of varying severity (5–7,19,20,51).…”

Section: Discussionmentioning

confidence: 99%

DLX5, FGF8 and the Pin1 isomerase control ΔNp63α protein stability during limb development: a regulatory loop at the basis of the SHFM and EEC congenital malformations

Restelli

Lopardo

Iacono

et al. 2014

Human Molecular Genetics

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Ectrodactyly, or Split-Hand/Foot Malformation (SHFM), is a congenital condition characterized by the loss of central rays of hands and feet. The p63 and the DLX5;DLX6 transcription factors, expressed in the embryonic limb buds and ectoderm, are disease genes for these conditions. Mutations of p63 also cause the ectodermal dysplasia–ectrodactyly–cleft lip/palate (EEC) syndrome, comprising SHFM. Ectrodactyly is linked to defects of the apical ectodermal ridge (AER) of the developing limb buds. FGF8 is the key signaling molecule in this process, able to direct proximo-distal growth and patterning of the skeletal primordial of the limbs. In the limb buds of both p63 and Dlx5;Dlx6 murine models of SHFM, the AER is poorly stratified and FGF8 expression is severely reduced. We show here that the FGF8 locus is a downstream target of DLX5 and that FGF8 counteracts Pin1–ΔNp63α interaction. In vivo, lack of Pin1 leads to accumulation of the p63 protein in the embryonic limbs and ectoderm. We show also that ΔNp63α protein stability is negatively regulated by the interaction with the prolyl-isomerase Pin1, via proteasome-mediated degradation; p63 mutant proteins associated with SHFM or EEC syndromes are resistant to Pin1 action. Thus, DLX5, p63, Pin1 and FGF8 participate to the same time- and location-restricted regulatory loop essential for AER stratification, hence for normal patterning and skeletal morphogenesis of the limb buds. These results shed new light on the molecular mechanisms at the basis of the SHFM and EEC limb malformations.

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“…Apart from proband 1, two further individuals have been reported with RHS phenotypes and a TP63 mutation in or near the DNA-binding domain; one presented with ectodermal dysplasia and syndactyly, but no cleft lip nor palate (Bougeard et al, 2003), and the other had ectodermal dysplasia, clefting, and bilateral clinodactyly V, but no ectrodactyly (Vera-Carbonell et al, 2012). Because of the location of the mutations in or near the DNAbinding domain, we would suggest for our proband 1 and these two patients a final diagnosis of 'incomplete EEC3 syndrome', reserving the term RHS for those individuals with mutations in the TP63 SAM domain.…”

Section: Discussionmentioning

confidence: 99%

A recurrent TP63 mutation causing EEC3 and Rapp–Hodgkin syndromes

Brueggemann

Bartsch

2016

Clinical Dysmorphology

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The ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (EEC3; OMIM #604292), the Rapp-Hodgkin syndrome (RHS), and various other syndromes are caused by mutations in the TP63 gene, which encodes a p53-like transcription factor. Here, we report on a woman aged 37 years and her daughter aged 3 years with the previously reported c.1028G>A (p.Arg343Gln) mutation in exon 8 of TP63. The mother lacked ectrodactyly, indicating a diagnosis of RHS, whereas the girl presented with all three major features (ectrodactyly, ectodermal dysplasia, clefting) and different minor features (including small and brittle nails, and recurrent conjunctivitis believed to be because of stenotic and blocked nasolacrimal ducts) of the EEC3 syndrome. The EEC and EEC-like syndromes are usually distinguished on the basis of the clinical findings; however, these syndromes show a huge variability in features because of variable expressivity and incomplete penetrance, making the correct clinical assignment difficult. In EEC3 syndrome and RHS, a clustering of mutations in the different domains of TP63 can be observed. Our findings indicate the clinical variability with TP63 mutations and underline that in the case of two syndromes being clinically possible in a patient, the final diagnosis should be assigned only after molecular diagnostics.

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Rapp–Hodgkin syndrome and SHFM1 patients: Delineating the p63–Dlx5/Dlx6 pathway

Cited by 15 publications

References 38 publications

Molecular mechanisms underlying nuchal hump formation in dolphin cichlid, Cyrtocara moorii

Molecular mechanisms underlying nuchal hump formation in dolphin cichlid, Cyrtocara moorii

DLX5, FGF8 and the Pin1 isomerase control ΔNp63α protein stability during limb development: a regulatory loop at the basis of the SHFM and EEC congenital malformations

A recurrent TP63 mutation causing EEC3 and Rapp–Hodgkin syndromes

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