Limbal Stem Cell Deficiency and Ocular Phenotype in Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome Caused by p63 Mutations

Iorio, Enzo Di; Kaye, Stephen B.; Ponzin, Diego; Barbaro, V.; Ferrari, Stefano; Böhm, Elisabetta; Nardiello, Paola; Castaldo, Giuseppe; McGrath, John A.; Willoughby, Colin E.

doi:10.1016/j.ophtha.2011.06.044

Cited by 94 publications

(76 citation statements)

References 41 publications

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“…In addition to skin defects, EEC patients suffer from visual morbidity with progressive limbal stem-cell deficiency that leads to severe visual impairments and blindness (7,8). Therefore, modeling of these diseases is essential to identify abnormalities in molecular processes involving p63, their effects on cell growth and skin development, and for drug screening.…”

mentioning

confidence: 99%

Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1 ^MET

Shalom-Feuerstein

Serror

Aberdam

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Ectodermal dysplasia is a group of congenital syndromes affecting a variety of ectodermal derivatives. Among them, ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome is caused by single point mutations in the p63 gene, which controls epidermal development and homeostasis. Phenotypic defects of the EEC syndrome include skin defects and limbal stem-cell deficiency. In this study, we designed a unique cellular model that recapitulated major embryonic defects related to EEC. Fibroblasts from healthy donors and EEC patients carrying two different point mutations in the DNA binding domain of p63 were reprogrammed into induced pluripotent stem cell (iPSC) lines. EEC-iPSC from both patients showed early ectodermal commitment into K18 + cells but failed to further differentiate into K14 + cells (epidermis/limbus) or K3/K12 + cells (corneal epithelium). APR-246 (PRIMA-1 MET ), a small compound that restores functionality of mutant p53 in human tumor cells, could revert corneal epithelial lineage commitment and reinstate a normal p63-related signaling pathway. This study illustrates the relevance of iPSC for p63 related disorders and paves the way for future therapy of EEC.

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mentioning

confidence: 99%

Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1 ^MET

Shalom-Feuerstein

Serror

Aberdam

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Among other risk factors for the severity and progression of the disease are recurrent infections from lacrimal drainage obstruction and tear film instability [18]. Most recently, Di Lorio [23] has described the ocular phenotype of 23 cases through EEC syndrome. According to what they reported in their study, EEC results from heterozygous missense mutations in the DNA--binding domain of the p63 gene, which is known to be a crucial element during embryogenesis and stem cell differentiation of stratified epithelia.…”

Section: Discussionmentioning

confidence: 99%

Ophthalmic Manifestations in Patients with Ectodermal Dysplasia Syndromes

Keklíkçí¹,

Yavuz²,

Tunik³

et al. 2014

Adv Clin Exp Med

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Background. Ectodermal dysplasia (ED) is a disorder that results from abnormal formation of at least two of the four major ectodermal derivatives in the developing embryo. The ectoderm of the embryo forms the skin, teeth, hair and nails, sweat glands and part of the eyes. Objectives. The aim of this article is to reveal ophthalmologic symptoms and signs as multidisciplinary, reliable criteria for ectodermal dysplasia. Material and Methods. In this retrospective study, 24 patients with ED were analyzed from the recorded data. Ophthalmological examination of the patients, who had previously received the diagnosis of ED in the dental department, was done. During the examination, ocular symptoms related to tear film, corneal changes, lacrimal duct, periorbital hyperpigmentation, alteration lashes and eyebrows were evaluated. Results. The age ranged between 3-45, and the mean and standard deviation (Mean ± SD) was 15.8 ± 7.4 years. The number of males was 13 (54.2%) and females, 11 (45.8%). Eighteen patients (75.0%) suffered from ocular complaints related to the ocular surface. In 11 of the patients with ED, there were dry eye symptoms. While the mean age of cases with eye involvement was 17.5, it was 23.1 in cases with dry eye symptoms. Conclusions. In the study, it was observed that, in patients with ED, ocular complaints, particularly dry eye symptoms, may increase as age advances (Adv Clin Exp Med 2014, 23, 4, 605-610).

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“…U człowieka może być on elementem zespołów zwią-zanych z mutacjami genu PAX6, takich jak wrodzony brak tęczówki [33,34] czy anomalia Petersa [35]. Innymi genetycznymi zaburzeniami, w których wykazano związek z niedoborem LESC, są: zespół EEC (ektrodaktylia, dysplazja ektodermalna, rozszczep wargi i podniebienia) [36,37], zespół KID (zapalenie rogówki, rybia łuska, głuchota) [38], skóra pergaminowa [39], dziedziczone autosomalnie dominująco zapalenie rogówki [40], zespół Turnera [41], wrodzona dyskeratoza [42,43,44] oraz zapalenie rogówki związane z zespołem niedoczynności wielogruczoło-wej [45,46]. Częstymi wtórnymi przyczynami LSCD są oparzenia chemiczne i termiczne powierzchni gałki ocznej oraz stany po uprzednich zabiegach operacyjnych lub krioterapii w obszarze rąbka rogówki [47,48].…”

Section: Choroby Rąbka Rogówki Związane Z Niedoborem Lescunclassified

Limbal epithelial stem cells in regeneration of corneal epithelium – clinical and molecular aspects

Sikora

Skubis

Sedlak

et al. 2018

Ann. Acad. Med. Siles.

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ST R ES ZCZ E NI EKomórki macierzyste rąbka rogówki (limbal epithelial stem cells -LESC) zlokalizowane są na granicy rogówki i spojówki. Ich funkcja polega na odbudowie rogówki poprzez zastępowanie uszkodzonych lub niefunkcjonalnych komórek. W niniejszej pracy zawarto informacje dotyczące charakterystyki LESC, opisano sposoby ich identyfikacji z wykorzystaniem markerów powierzchniowych oraz cech morfologicznych. W pracy zawarto również informacje dotyczące hodowli komórek w warunkach in vitro jako potencjalnego źródła komórek wykorzystywanych w terapii oraz poruszono zagadnienia dysfunkcji LESC spowodowanych niedoborem komórek macierzystych wywołanych różnymi czynnikami, a także przedstawiono stosowane obecnie metody leczenia LSCD (limbal stem cell deficiency). Standardowe leczenie niedoboru komórek macierzystych rąbka rogówki polega na farmakoterapii oraz transplantacji autologicznego rąbka rogówki bogatego w komórki macierzyste. W przypadku całkowitego niedoboru LESC konieczne jest wykonanie przeszczepów allogenicznych.

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Limbal Stem Cell Deficiency and Ocular Phenotype in Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome Caused by p63 Mutations

Cited by 94 publications

References 41 publications

Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1 ^MET

Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1 ^MET

Ophthalmic Manifestations in Patients with Ectodermal Dysplasia Syndromes

Limbal epithelial stem cells in regeneration of corneal epithelium – clinical and molecular aspects

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Limbal Stem Cell Deficiency and Ocular Phenotype in Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome Caused by p63 Mutations

Cited by 94 publications

References 41 publications

Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1 MET

Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1 MET

Ophthalmic Manifestations in Patients with Ectodermal Dysplasia Syndromes

Limbal epithelial stem cells in regeneration of corneal epithelium – clinical and molecular aspects

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Product

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Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1 ^MET

Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1 ^MET