Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/113513
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Type: Journal article
Title: Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery
Author: Kumar, R.
Gardner, A.
Homan, C.
Douglas, E.
Mefford, H.
Wieczorek, D.
Lüdecke, H.-.J.
Stark, Z.
Sadedin, S.
Nowak, C.
Douglas, J.
Parsons, G.
Mark, P.
Loidi, L.
Herman, G.
Mihalic Mosher, T.
Gillespie, M.
Brady, L.
Tarnopolsky, M.
Madrigal, I.
et al.
Citation: Human mutation, 2018; 39(8):1126-1138
Publisher: Wiley
Issue Date: 2018
ISSN: 1059-7794
1098-1004
Statement of
Responsibility: 
Raman Kumar, Alison Gardner, Claire C. Homan, Evelyn Douglas, Heather Mefford, Dagmar Wieczorek, Hermann-Josef Lüdecke, Zornitza Stark, Simon Sadedin, The Broad CMG, Catherine Bearce Nowak, Jessica Douglas, Gretchen Parsons, Paul Mark, Lourdes Loidi, Gail E. Herman, Theresa Mihalic Mosher, Meredith K. Gillespie, Lauren Brady, Mark Tarnopolsky, Irene Madrigal, Jesús Eiris, Laura Domènech Salgado, Raquel Rabionet, Tim M. Strom, Naoko Ishihara, Hidehito Inagaki, Hiroki Kurahashi, Tracy Dudding-Byth, Elizabeth E. Palmer, Michael Field, Jozef Gecz
Abstract: Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and three maternally-inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum. These comprise three rare missense THOC2 variants that affect evolutionarily conserved amino acid residues and reduce protein stability and two with canonical splice-site THOC2 variants that result in C-terminally truncated THOC2 proteins. We present detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe neurocognitive features, including movement and seizure disorders were observed in this cohort. Taken together our data show that even subtle alterations to the canonical molecular pathways such as mRNA export, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in humans. This article is protected by copyright. All rights reserved.
Keywords: Partial loss-of-function variants; mRNA export; protein stability; THOC2; XLID
Rights: © 2018 Wiley Periodicals, Inc.
RMID: 0030090335
DOI: 10.1002/humu.23557
Grant ID: http://purl.org/au-research/grants/nhmrc/1091593
http://purl.org/au-research/grants/nhmrc/1041920
Appears in Collections:Medicine publications

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