Ankyloblepharon-ectodermal defects-cleft lip-palate syndrome due to a novel missense mutation in the SAM domain of the <i>TP63</i> gene

Tajir, Mariam; Lyahyai, Jaber; Guaoua, Soukaina; Alloussi, Mustapha El; Sefiani, Abdelaziz

doi:10.2478/bjmg-2020-0013

Cited by 7 publications

(5 citation statements)

References 13 publications

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“…Differential diagnosis should consider also EEC and Rapp–Hodgkin syndrome, both of which have many common features with AEC [ 18 ]. The presence of ankyloblepharon and erosive scalp lesions in most cases differentiates AEC from the other two syndromes, although some rare cases with overlapping clinical phenotypes have been reported [ 19 , 20 ]. In most instances, severe limb malformations, such as ectrodactyly, are present only in EEC patients.…”

Section: Discussionmentioning

confidence: 99%

“…A point mutation c.1798G>C has been reported in an AEC case affecting the same codon by causing an amino acid substitution G600R (p.Gly600Arg) in the SAM domain [ 19 ]. In addition, there are other patients with AEC syndrome that also have amino acid substitutions similar to our patient (i.e., Glycine to Valine), in the same region of the SAM domain known to mediate protein–protein interactions [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

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Molecular Modeling Analysis Provides Genotype–Phenotype Correlation Insights in a Patient with Ankyloblepharon-Ectodermal Dysplasia-Clefting Syndrome

Douka

Goutzanis

Vlachakis

et al. 2023

Genes

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Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is a rare autosomal dominant disorder. AEC is caused by mutations in the TP63 gene that encodes the tumor suppressor p63 protein, itself involved in the regulation of epidermal proliferation, development, and differentiation. We present here a typical AEC case of a four-year-old girl with extensive skin erosions and erythroderma of the scalp and the trunk, and to a lesser extent of the limbs, nail dystrophy on the fingers and toes, xerophthalmia, a high-arched palate, oligodontia, and hypohidrosis. Mutation analysis of the TP63 gene detected a de novo missense mutation in exon 14 (c.1799G>T; p.Gly600Val). We discuss the phenotype–genotype correlation by presenting the clinical features of AEC in the patient, and the effect of the detected mutation in p63 structure and function using protein structural modeling, in view of similar cases in the literature. We performed a molecular modeling study in order to link the effect on the protein structure level of the missense mutation G600V. We noted that the introduction of the bulkier Valine residue in place of the slim Glycine residue caused a significantly altered 3D conformational arrangement of that protein region, pushing away the adjacent antiparallel α helix. We propose that the introduced locally altered structure of the G600V mutant p63 has a significant functional effect on specific protein–protein interactions, thus affecting the clinical phenotype.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Molecular Modeling Analysis Provides Genotype–Phenotype Correlation Insights in a Patient with Ankyloblepharon-Ectodermal Dysplasia-Clefting Syndrome

Douka

Goutzanis

Vlachakis

et al. 2023

Genes

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“…An early diagnosis of AEC syndrome is crucial in order to implement appropriate genetic counseling to parents, to define their genetic profile and to identify, as early as possible, those who would benefit from primary and/or secondary prevention of disease [ 22 ]. It is necessary to provide update and complete information on potential risks to offspring, and on reproductive options to young adults who are affected or at risk.…”

Section: Discussionmentioning

confidence: 99%

Novel missense mutation of the TP63 gene in a newborn with Hay-Wells/Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndrome: clinical report and follow-up

et al. 2021

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Introduction Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, also known as Hay-Wells syndrome, is a rare genetic syndrome with ectodermal dysplasia. About 100 patients have been reported to date. It is associated to a heterozygous mutation of the tumor protein p63 (TP63) gene, located on chromosome 3q28. Typical clinical manifestations include: filiform ankyloblepharon adnatum (congenital adherence of the eyelids), ectodermal abnormalities (sparse and frizzy hair, skin defects, nail alterations, dental changes and hypohidrosis), and cleft lip/palate. Diagnostic suspicion is based on clinical signs and confirmed by genetic testing. Patient’s presentation We hereby report on a female newborn with erythroderma, thin lamellar desquamations, extensive skin erosions, sparse and wiry hair, filiform ankyloblepharon adnatum, agenesis of the lachrymal puncta, cleft palate and nail dysplasia. Her phenotype was compatible with AEC syndrome. Then, based on the clinical suspicion, sequencing analysis of the TP63 gene was performed, and revealed a de novo novel missense mutation. Eyelids adherence and cleft palate underwent surgical correction, while skin erosions were treated with topical antibiotics/antifungals and emollient/re-epithelizing creams. A surgical reconstruction is presently planned for the agenesis of the lachrymal puncta. The infant currently is 17 months of age and is included in a multidisciplinary follow-up. At present shows growth impairment and mild developmental delay, and typical signs of ectodermal dysplasia with small areas of dermatitis lesions on the scalp, without further abnormalities. Conclusions Our report underlines the relevance of an early and careful clinical evaluation in neonates with ankyloblefaron, facial dysmorphism, and signs of ectodermal dysplasia. In these cases, the suspicion of AEC syndrome must be promptly raised, and sequencing analysis of TP63 early performed as well. An individualized, multidisciplinary and long-term follow-up should be guaranteed to affected subjects and their families, also to identify associated morbidities and prevent possible serious complications and adverse outcomes.

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“…Point mutations in the DBD result in EEC (ectrodactyly-ectodermal dysplasiacleft) syndrome, which is characterized by limb deformation, cleft lip and palate, and ectodermal dysplasia [49]. Mutations in the SAM and TID domains of the TP63 C-terminus are responsible for ankyloblepharon, ectodermal defects, and cleft lip/palate syndrome (AEC) [50]. Patients with AEC suffer from severe skin erosions at or after birth.…”

Section: Humanmentioning

confidence: 99%

The Role of Mutant p63 in Female Fertility

Luan

et al. 2021

IJMS

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The transcription factor p63, one of the p53 family members, plays an essential role in regulating maternal reproduction and genomic integrity as well as epidermal development. TP63 (human)/Trp63 (mouse) produces multiple isoforms: TAp63 and ΔNp63, which possess a different N-terminus depending on two different promoters, and p63a, p63b, p63g, p63δ, and p63ε as products of alternative splicing at the C-terminus. TAp63 expression turns on in the nuclei of primordial germ cells in females and is maintained mainly in the oocyte nuclei of immature follicles. It has been established that TAp63 is the genomic guardian in oocytes of the female ovaries and plays a central role in determining the oocyte fate upon oocyte damage. Lately, there is increasing evidence that TP63 mutations are connected with female infertility, including isolated premature ovarian insufficiency (POI) and syndromic POI. Here, we review the biological functions of p63 in females and discuss the consequences of p63 mutations, which result in infertility in human patients.

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Ankyloblepharon-ectodermal defects-cleft lip-palate syndrome due to a novel missense mutation in the SAM domain of the TP63 gene

Cited by 7 publications

References 13 publications

Molecular Modeling Analysis Provides Genotype–Phenotype Correlation Insights in a Patient with Ankyloblepharon-Ectodermal Dysplasia-Clefting Syndrome

Molecular Modeling Analysis Provides Genotype–Phenotype Correlation Insights in a Patient with Ankyloblepharon-Ectodermal Dysplasia-Clefting Syndrome

Novel missense mutation of the TP63 gene in a newborn with Hay-Wells/Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndrome: clinical report and follow-up

The Role of Mutant p63 in Female Fertility

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