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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
Growth disorders
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:
It is part of: Human Mutation, 2018, vol. 39, num. 8, p. 1126-1138
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ISSN: 1059-7794
Appears in Collections:Articles publicats en revistes (Genètica, Microbiologia i Estadística)

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