Expanding Clinical Presentations Due to Variations in THOC2 mRNA Nuclear Export Factor
dc.contributor.author | Kumar, R | |
dc.contributor.author | Palmer, E | |
dc.contributor.author | Gardner, AE | |
dc.contributor.author | Carroll, R | |
dc.contributor.author | Banka, S | |
dc.contributor.author | Abdelhadi, O | |
dc.contributor.author | Donnai, D | |
dc.contributor.author | Elgersma, Y | |
dc.contributor.author | Curry, CJ | |
dc.contributor.author | Gardham, A | |
dc.contributor.author | Suri, M | |
dc.contributor.author | Malla, R | |
dc.contributor.author | Brady, LI | |
dc.contributor.author | Tarnopolsky, M | |
dc.contributor.author | Azmanov, DN | |
dc.contributor.author | Atkinson, V | |
dc.contributor.author | Black, M | |
dc.contributor.author | Baynam, G | |
dc.contributor.author | Dreyer, L | |
dc.contributor.author | Hayeems, RZ | |
dc.contributor.author | Marshall, CR | |
dc.contributor.author | Costain, G | |
dc.contributor.author | Wessels, MW | |
dc.contributor.author | Baptista, Julia | |
dc.contributor.author | Drummond, J | |
dc.contributor.author | Leffler, M | |
dc.contributor.author | Field, M | |
dc.contributor.author | Gecz, J | |
dc.date.accessioned | 2022-05-03T18:03:20Z | |
dc.date.issued | 2020-02-11 | |
dc.identifier.issn | 1662-5099 | |
dc.identifier.issn | 1662-5099 | |
dc.identifier.other | ARTN 12 | |
dc.identifier.uri | http://hdl.handle.net/10026.1/19165 | |
dc.description.abstract |
Multiple TREX mRNA export complex subunits (e.g., THOC1, THOC2, THOC5, THOC6, THOC7) have now been implicated in neurodevelopmental disorders (NDDs), neurodegeneration and cancer. We previously implicated missense and splicing-defective THOC2 variants in NDDs and a broad range of other clinical features. Here we report 10 individuals from nine families with rare missense THOC2 variants including the first case of a recurrent variant (p.Arg77Cys), and an additional individual with an intragenic THOC2 microdeletion (Del-Ex37-38). Ex vivo missense variant testing and patient-derived cell line data from current and published studies show 9 of the 14 missense THOC2 variants result in reduced protein stability. The splicing-defective and deletion variants result in a loss of small regions of the C-terminal THOC2 RNA binding domain (RBD). Interestingly, reduced stability of THOC2 variant proteins has a flow-on effect on the stability of the multi-protein TREX complex; specifically on the other NDD-associated THOC subunits. Our current, expanded cohort refines the core phenotype of THOC2 NDDs to language disorder and/or ID, with a variable severity, and disorders of growth. A subset of affected individuals' has severe-profound ID, persistent hypotonia and respiratory abnormalities. Further investigations to elucidate the pathophysiological basis for this severe phenotype are warranted. | |
dc.format.extent | 12- | |
dc.format.medium | Electronic-eCollection | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | Frontiers Media SA | |
dc.subject | mRNA export | |
dc.subject | THOC2 | |
dc.subject | intellectual disability | |
dc.subject | neurodevelopmental disorders | |
dc.subject | microdeletion | |
dc.title | Expanding Clinical Presentations Due to Variations in THOC2 mRNA Nuclear Export Factor | |
dc.type | journal-article | |
dc.type | Journal Article | |
plymouth.author-url | https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000517521500001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=11bb513d99f797142bcfeffcc58ea008 | |
plymouth.volume | 13 | |
plymouth.publication-status | Published online | |
plymouth.journal | Frontiers in Molecular Neuroscience | |
dc.identifier.doi | 10.3389/fnmol.2020.00012 | |
plymouth.organisational-group | /Plymouth | |
plymouth.organisational-group | /Plymouth/Faculty of Health | |
plymouth.organisational-group | /Plymouth/Faculty of Health/Peninsula Medical School | |
plymouth.organisational-group | /Plymouth/Users by role | |
plymouth.organisational-group | /Plymouth/Users by role/Academics | |
dc.publisher.place | Switzerland | |
dcterms.dateAccepted | 2020-01-15 | |
dc.rights.embargodate | 9999-12-31 | |
dc.identifier.eissn | 1662-5099 | |
dc.rights.embargoperiod | Not known | |
rioxxterms.versionofrecord | 10.3389/fnmol.2020.00012 | |
rioxxterms.licenseref.uri | http://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2020 | |
rioxxterms.type | Journal Article/Review |