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

The Broad CMG

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1126-1138
Number of pages13
JournalHuman Mutation
Volume39
Issue number8
DOIs
Publication statusPublished - 08-2018

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Growth Disorders
Cell Nucleus Active Transport
Messenger RNA
X-Linked Genes
Protein Stability
Movement Disorders
Brain Diseases
Cell Nucleus
Intellectual Disability
Virulence
Epilepsy
Cytoplasm
Amino Acids
Neurocognitive Disorders
Proteins
Neurodevelopmental Disorders

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

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title = "Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery",
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.",
author = "{The Broad CMG} and Raman Kumar and Alison Gardner and Homan, {Claire C.} and Evelyn Douglas and Heather Mefford and Dagmar Wieczorek and L{\"u}decke, {Hermann Josef} and Zornitza Stark and Simon Sadedin and Nowak, {Catherine Bearce} and Jessica Douglas and Gretchen Parsons and Paul Mark and Lourdes Loidi and Herman, {Gail E.} and {Mihalic Mosher}, Theresa and Gillespie, {Meredith K.} and Lauren Brady and Mark Tarnopolsky and Irene Madrigal and Jes{\'u}s Eiris and {Dom{\`e}nech Salgado}, Laura and Raquel Rabionet and Strom, {Tim M.} and Naoko Ishihara and Hidehito Inagaki and Hiroki Kurahashi and Tracy Dudding-Byth and Palmer, {Elizabeth E.} and Michael Field and Jozef Gecz",
year = "2018",
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language = "English",
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pages = "1126--1138",
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Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery. / The Broad CMG.

In: Human Mutation, Vol. 39, No. 8, 08.2018, p. 1126-1138.

Research output: Contribution to journalArticle

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T1 - Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery

AU - The Broad CMG

AU - Kumar, Raman

AU - Gardner, Alison

AU - Homan, Claire C.

AU - Douglas, Evelyn

AU - Mefford, Heather

AU - Wieczorek, Dagmar

AU - Lüdecke, Hermann Josef

AU - Stark, Zornitza

AU - Sadedin, Simon

AU - Nowak, Catherine Bearce

AU - Douglas, Jessica

AU - Parsons, Gretchen

AU - Mark, Paul

AU - Loidi, Lourdes

AU - Herman, Gail E.

AU - Mihalic Mosher, Theresa

AU - Gillespie, Meredith K.

AU - Brady, Lauren

AU - Tarnopolsky, Mark

AU - Madrigal, Irene

AU - Eiris, Jesús

AU - Domènech Salgado, Laura

AU - Rabionet, Raquel

AU - Strom, Tim M.

AU - Ishihara, Naoko

AU - Inagaki, Hidehito

AU - Kurahashi, Hiroki

AU - Dudding-Byth, Tracy

AU - Palmer, Elizabeth E.

AU - Field, Michael

AU - Gecz, Jozef

PY - 2018/8

Y1 - 2018/8

N2 - 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.

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