Functional and clinical analysis of five EDA variants associated with ectodermal dysplasia but with a hard-to-predict significance

dc.contributor.authorGökdere, Sare
dc.contributor.authorSchneider, Holm
dc.contributor.authorHehr, Ute
dc.contributor.authorWillen, Laure
dc.contributor.authorSchneider, Pascal
dc.contributor.authorMaier-Wohlfart, Sigrun
dc.date.accessioned2022-08-03
dc.date.available2023-10-09T19:05:30Z
dc.date.created2022
dc.date.issued2022-08-03
dc.description.abstractDeficiency 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.en
dc.identifier.citationFrontiers in Genetics 13 (2022): 934395. <https://www.frontiersin.org/articles/10.3389/fgene.2022.934395/full>
dc.identifier.doihttps://doi.org/10.3389/fgene.2022.934395
dc.identifier.issn1664-8021
dc.identifier.opus-id19928
dc.identifier.urihttps://open.fau.de/handle/openfau/19928
dc.identifier.urnurn:nbn:de:bvb:29-opus4-199280
dc.language.isoen
dc.publisherFrontiers Media S.A.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/deed.de
dc.subjectX-linked hypohidrotic ectodermal dysplasia
dc.subjectectodysplasin A
dc.subjectvariants of uncertain significance
dc.subjectfunctional studies
dc.subjectserum EDA concentration
dc.subjectgenotype-phenotype correlation
dc.subject.ddcDDC Classification::6 Technik, Medizin, angewandte Wissenschaften :: 61 Medizin und Gesundheit :: 610 Medizin und Gesundheit
dc.titleFunctional and clinical analysis of five EDA variants associated with ectodermal dysplasia but with a hard-to-predict significanceen
dc.typearticle
dcterms.publisherFriedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
local.date.prevpublished2022-07-18
local.document.articlenumber934395
local.journal.titleFrontiers in Genetics
local.journal.volume13
local.sendToDnbfree*
local.subject.fakultaetMedizinische Fakultät
local.subject.importimport
local.subject.sammlungUniversität Erlangen-Nürnberg / Eingespielte Open Access Artikel / Eingespielte Open Access Artikel 2022
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