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http://hdl.handle.net/2445/163797
Title: | Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery |
Author: | Kumar, Raman Gardner, Alison Homan, Claire C. Douglas, Evelyn Mefford, Heather Wieczorek, Dagmar Luedecke, Hermann-Josef Stark, Zornitza Sadedin, Simon Nowak, Catherine Bearce Douglas, Jessica Parsons, Gretchen Mark, Paul Loidi, Lourdes Herman, Gail E. Mihalic Mosher, Theresa Gillespie, Meredith K. Brady, Lauren Tarnopolsky, Mark Madrigal Bajo, Irene Eiris, Jesus Domenech Salgado, Laura Rabionet Janssen, Raquel Strom, Tim M. Ishihara, Naoko Inagaki, Hidehito Kurahashi, Hiroki Dudding-Byth, Tracy Palmer, Elizabeth E. Field, Michael Gecz, Jozef |
Keywords: | Trastorns del creixement Neurologia Growth disorders Neurology |
Issue Date: | 31-May-2018 |
Publisher: | Wiley |
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 threematernally 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 asmRNAexport, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in humans |
Note: | Versió postprint del document publicat a: https://doi.org/10.1002/humu.23557 |
It is part of: | Human Mutation, 2018, vol. 39, num. 8, p. 1126-1138 |
URI: | http://hdl.handle.net/2445/163797 |
Related resource: | https://doi.org/10.1002/humu.23557 |
ISSN: | 1059-7794 |
Appears in Collections: | Articles publicats en revistes (Genètica, Microbiologia i Estadística) |
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