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dc.contributor.authorRawlins, Lettie E
dc.contributor.authorAlmousa, Hashem
dc.contributor.authorKhan, Shazia
dc.contributor.authorCollins, Stephan C
dc.contributor.authorMilev, Miroslav P
dc.contributor.authorLeslie, Joseph
dc.contributor.authorSaint-Dic, Djenann
dc.contributor.authorKhan, Valeed
dc.contributor.authorHincapie, Ana Maria
dc.contributor.authorDay, Jacob O
dc.contributor.authorMcGavin, Lucy
dc.contributor.authorRowley, Christine
dc.contributor.authorHarlalka, Gaurav V
dc.contributor.authorVancollie, Valerie E
dc.contributor.authorAhmad, Wasim
dc.contributor.authorLelliott, Christopher
dc.contributor.authorGul, Asma
dc.contributor.authorYalcin, Binnaz
dc.contributor.authorCrosby, Andrew H
dc.contributor.authorSacher, Michael
dc.contributor.authorBaple, Emma L
dc.date.accessioned2022-05-06T23:30:52Z
dc.date.available2022-05-06T23:30:52Z
dc.date.issued2022-03
dc.identifier.issn1553-7404
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/336807
dc.description.abstractThe highly evolutionarily conserved transport protein particle (TRAPP) complexes (TRAPP II and III) perform fundamental roles in subcellular trafficking pathways. Here we identified biallelic variants in TRAPPC10, a component of the TRAPP II complex, in individuals with a severe microcephalic neurodevelopmental disorder. Molecular studies revealed a weakened interaction between mutant TRAPPC10 and its putative adaptor protein TRAPPC2L. Studies of patient lymphoblastoid cells revealed an absence of TRAPPC10 alongside a concomitant absence of TRAPPC9, another key TRAPP II complex component associated with a clinically overlapping neurodevelopmental disorder. The TRAPPC9/10 reduction phenotype was recapitulated in TRAPPC10-/- knockout cells, which also displayed a membrane trafficking defect. Notably, both the reduction in TRAPPC9 levels and the trafficking defect in these cells could be rescued by wild type but not mutant TRAPPC10 gene constructs. Moreover, studies of Trappc10-/- knockout mice revealed neuroanatomical brain defects and microcephaly, paralleling findings seen in the human condition as well as in a Trappc9-/- mouse model. Together these studies confirm autosomal recessive TRAPPC10 variants as a cause of human disease and define TRAPP-mediated pathomolecular outcomes of importance to TRAPPC9 and TRAPPC10 mediated neurodevelopmental disorders in humans and mice.
dc.format.mediumElectronic-eCollection
dc.publisherPublic Library of Science (PLoS)
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectMicrocephaly
dc.subjectNeurodevelopmental Disorders
dc.subjectPhenotype
dc.titleBiallelic variants in TRAPPC10 cause a microcephalic TRAPPopathy disorder in humans and mice.
dc.typeArticle
dc.publisher.departmentDepartment of Clinical Biochemistry
dc.date.updated2022-05-06T10:41:39Z
prism.issueIdentifier3
prism.numberARTN e1010114
prism.publicationDate2022
prism.publicationNamePLoS Genet
prism.startingPagee1010114
prism.volume18
dc.identifier.doi10.17863/CAM.84226
dcterms.dateAccepted2022-02-20
rioxxterms.versionofrecord10.1371/journal.pgen.1010114
rioxxterms.versionVoR
dc.contributor.orcidRawlins, Lettie E [0000-0002-6764-253X]
dc.contributor.orcidAlmousa, Hashem [0000-0003-2679-5350]
dc.contributor.orcidCollins, Stephan C [0000-0002-1533-3380]
dc.contributor.orcidLeslie, Joseph [0000-0003-0972-8818]
dc.contributor.orcidSaint-Dic, Djenann [0000-0001-9328-7108]
dc.contributor.orcidKhan, Valeed [0000-0002-3840-5439]
dc.contributor.orcidDay, Jacob O [0000-0002-6020-510X]
dc.contributor.orcidHarlalka, Gaurav V [0000-0001-8968-2447]
dc.contributor.orcidVancollie, Valerie E [0000-0003-1547-1975]
dc.contributor.orcidLelliott, Christopher [0000-0001-8087-4530]
dc.contributor.orcidYalcin, Binnaz [0000-0002-1924-6807]
dc.contributor.orcidCrosby, Andrew H [0000-0003-3667-9054]
dc.contributor.orcidSacher, Michael [0000-0003-2926-5064]
dc.contributor.orcidBaple, Emma L [0000-0002-6637-3411]
dc.identifier.eissn1553-7404
rioxxterms.typeJournal Article/Review
cam.issuedOnline2022-03-17
cam.depositDate2022-05-06
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International