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Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation

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dc.contributor.authorPolla, Daniel L.
dc.contributor.authorEdmondson, Andrew C.
dc.contributor.authorDuvet, Sandrine
dc.contributor.authorMarch, Michael E.
dc.contributor.authorSousa, Ana Berta
dc.contributor.authorLehman, Anna
dc.contributor.authorNiyazov, Dmitriy
dc.contributor.authorvan Dijk, Fleur
dc.contributor.authorDemirdas, Serwet
dc.contributor.authorvan Slegtenhorst, Marjon A.
dc.contributor.authorKievit, Anneke J. A.
dc.contributor.authorSchulz, Celine
dc.contributor.authorArmstrong, Linlea
dc.contributor.authorBi, Xin
dc.contributor.authorRader, Daniel J.
dc.contributor.authorIzumi, Kosuke
dc.contributor.authorZackai, Elaine H.
dc.contributor.authorde Franco, Elisa
dc.contributor.authorJorge, Paula
dc.contributor.authorHuffels, Sophie C.
dc.contributor.authorHommersom, Marina
dc.contributor.authorEllard, Sian
dc.contributor.authorLefeber, Dirk J.
dc.contributor.authorSantani, Avni
dc.contributor.authorHand, Nicholas J.
dc.contributor.authorvan Bokhoven, Hans
dc.contributor.authorHe, Miao
dc.contributor.authorde Brouwer, Arjan P. M.
dc.date.accessioned2021-10-21T15:36:32Z
dc.date.available2021-10-21T15:36:32Z
dc.date.issued2021
dc.description© 2021 American Society of Human Geneticspt_PT
dc.description.abstractEDEM3 encodes a protein that converts Man8GlcNAc2 isomer B to Man7-5GlcNAc2. It is involved in the endoplasmic reticulum-associated degradation pathway, responsible for the recognition of misfolded proteins that will be targeted and translocated to the cytosol and degraded by the proteasome. In this study, through a combination of exome sequencing and gene matching, we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3. The affected individuals present with an inherited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable facial dysmorphisms. Experiments in human fibroblast cell lines, human plasma, and mouse plasma and brain tissue demonstrated decreased trimming of Man8GlcNAc2 isomer B to Man7GlcNAc2, consistent with loss of EDEM3 enzymatic activity. In human cells, Man5GlcNAc2 to Man4GlcNAc2 conversion is also diminished with an increase of Glc1Man5GlcNAc2. Furthermore, analysis of the unfolded protein response showed a reduced increase in EIF2AK3 (PERK) expression upon stimulation with tunicamycin as compared to controls, suggesting an impaired unfolded protein response. The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing. We propose to call this deficiency EDEM3-CDG.pt_PT
dc.description.sponsorshipThis work was supported by the EU FP7 large-scale integrating project Genetic and Epigenetic Networks in Cognitive Dysfunction (241995) (to H.v.B.); National Institutes of Health (NIH) grants 5R01GM115730-03 (to M.H.), U54 NS115198 (to A.C.E. and M.H.), and T32GM008638 (to A.C.E.); and the Transatlantic Network of Excellence grant (10CVD03) from the Fondation Leducq and NIH NHGRI U01HG006398 (to D.J.R.). Family 4 was enrolled in the CAUSES Study; investigators include Shelin Adam, Christele Du Souich, Alison Elliott, Anna Lehman, Jill Mwenifumbo, Tanya Nelson, Clara Van Karnebeek, and Jan Friedman; it is funded by Mining for Miracles, British Columbia Children’s Hospital Foundation (grant number F15-01355) and Genome British Columbia (grant number F16-02276). D.L.P. is recipient of a CAPES Fellowship (99999.013311/2013-01). X.B. is supported by an AHA career development award (19CDA34630032).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationAm J Hum Genet. 2021 Jul 1;108(7):1342-1349pt_PT
dc.identifier.doi10.1016/j.ajhg.2021.05.010pt_PT
dc.identifier.eissn1537-6605
dc.identifier.issn0002-9297
dc.identifier.urihttp://hdl.handle.net/10451/49979
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relationGenetic and Epigenetic Networks in Cognitive Dysfunction
dc.relation.publisherversionhttps://www.sciencedirect.com/journal/the-american-journal-of-human-geneticspt_PT
dc.subjectCDGpt_PT
dc.subjectEDEM3pt_PT
dc.subjectMannosidasept_PT
dc.subjectN-glycanpt_PT
dc.subjectDysmorphismpt_PT
dc.subjectHigh-mannosept_PT
dc.subjectMousept_PT
dc.titleBi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylationpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleGenetic and Epigenetic Networks in Cognitive Dysfunction
oaire.awardURIinfo:eu-repo/grantAgreement/EC/FP7/241995/EU
oaire.citation.endPage1349pt_PT
oaire.citation.issue7pt_PT
oaire.citation.startPage1342pt_PT
oaire.citation.titleThe American Journal of Human Geneticspt_PT
oaire.citation.volume108pt_PT
oaire.fundingStreamFP7
person.familyNameFonseca Vieira Álvares Sousa Ferrand Almeida
person.givenNameAna Berta
person.identifier.ciencia-id031D-CFAD-116A
person.identifier.orcid0000-0001-5889-2492
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameEuropean Commission
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication7763033e-aa1b-4f2b-ab30-3eba5815b1ee
relation.isAuthorOfPublication.latestForDiscovery7763033e-aa1b-4f2b-ab30-3eba5815b1ee
relation.isProjectOfPublicationee1cfc28-61ff-4bc5-af17-38ffaf0eb182
relation.isProjectOfPublication.latestForDiscoveryee1cfc28-61ff-4bc5-af17-38ffaf0eb182

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