Titre
Functional and clinical analysis of five EDA variants associated with ectodermal dysplasia but with a hard-to-predict significance.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Gökdere, S.
Auteure/Auteur
Schneider, H.
Auteure/Auteur
Hehr, U.
Auteure/Auteur
Willen, L.
Auteure/Auteur
Schneider, P.
Auteure/Auteur
Maier-Wohlfart, S.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1664-8021
Statut éditorial
Publié
Date de publication
2022
Volume
13
Première page
934395
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Publication Status: epublish
Résumé
Deficiency of ectodysplasin A1 (EDA1) due to variants of the gene EDA causes X-linked hypohidrotic ectodermal dysplasia (XLHED), a rare genetic condition characterized by abnormal development of ectodermal structures. XLHED is defined by the triad of hypotrichosis, hypo- or anhidrosis, and hypo- or anodontia. Anhidrosis may lead to life-threatening hyperthermia. A definite genetic diagnosis is, thus, important for the patients' management and amenability to a novel prenatal treatment option. Here, we describe five familial EDA variants segregating with the disease in three families, for which different prediction tools yielded discordant results with respect to their significance. Functional properties in vitro and levels of circulating serum EDA were compared with phenotypic data on skin, hair, eyes, teeth, and sweat glands. EDA1-Gly176Val, although associated with relevant hypohidrosis, still bound to the EDA receptor (EDAR). Subjects with EDA1-Pro389LeufsX27, -Ter392GlnfsX30, -Ser125Cys, and an EDA1 splice variant (c.924+7A > G) showed complete absence of pilocarpine-induced sweating. EDA1-Pro389LeufsX27 was incapable of binding to EDAR and undetectable in serum. EDA1-Ter392GlnfsX30, produced in much lower amounts than wild-type EDA1, could still bind to EDAR, and so did EDA1-Ser125Cys that was, however, undetectable in serum. The EDA splice variant c.924+7A > G resulted experimentally in a mix of wild-type EDA1 and EDA molecules truncated in the middle of the receptor-binding domain, with reduced EDA serum concentration. Thus, in vitro assays reflected the clinical phenotype in two of these difficult cases, but underestimated it in three others. Absence of circulating EDA seems to predict the full-blown phenotype of XLHED, while residual EDA levels may also be found in anhidrotic patients. This indicates that unborn subjects carrying variants of uncertain significance could benefit from an upcoming prenatal medical treatment even if circulating EDA levels or tests in vitro suggest residual EDA1 activity.
PID Serval
serval:BIB_30C88A426776
PMID
Open Access
Oui
Date de création
2022-08-24T07:37:10.284Z
Date de création dans IRIS
2025-05-20T18:54:15Z
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Nom
35923710_BIB_30C88A426776.pdf
Version du manuscrit
published
Licence
https://creativecommons.org/licenses/by/4.0
Taille
2.28 MB
Format
Adobe PDF
PID Serval
serval:BIB_30C88A426776.P001
URN
urn:nbn:ch:serval-BIB_30C88A4267765
Somme de contrôle
(MD5):611fc2a070548fd85f879d0c3e6c613a