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2018-05-31

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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/163797

Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery

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https://doi.org/10.1002/humu.23557

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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

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Trastorns del creixement, Neurologia

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Growth disorders, Neurology

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Articles publicats en revistes (Genètica, Microbiologia i Estadística)

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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. Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery. _Human Mutation_. 2018. Vol. 39, núm. 8, pàgs. 1126-1138. [consulta: 25 de febrer de 2026]. ISSN: 1059-7794. [Disponible a: https://hdl.handle.net/2445/163797]

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