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

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.

[1]  B. D. de Vries,et al.  Computer face-matching technology using two-dimensional photographs accurately matches the facial gestalt of unrelated individuals with the same syndromic form of intellectual disability , 2017, BMC Biotechnology.

[2]  Tomas W. Fitzgerald,et al.  Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1133 families with developmental disorders , 2017, Genetics in Medicine.

[3]  J. Rosenfeld,et al.  A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations. , 2017, American journal of human genetics.

[4]  R. Bowser,et al.  ALS Associated Mutations in Matrin 3 Alter Protein-Protein Interactions and Impede mRNA Nuclear Export , 2017, Scientific Reports.

[5]  Devin P. Sullivan,et al.  A subcellular map of the human proteome , 2017, Science.

[6]  J. Rivière,et al.  Autosomal recessive mutations in THOC6 cause intellectual disability: syndrome delineation requiring forward and reverse phenotyping , 2017, Clinical genetics.

[7]  Stuart A. Wilson,et al.  The role of TREX in gene expression and disease , 2016, The Biochemical journal.

[8]  Steve D. M. Brown,et al.  High-throughput discovery of novel developmental phenotypes , 2017 .

[9]  J. Rosenfeld,et al.  De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females , 2016, Molecular Psychiatry.

[10]  D. Cook,et al.  Mortality Among Adults With Intellectual Disability in England: Comparisons With the General Population. , 2016, American journal of public health.

[11]  Orrin Devinsky,et al.  De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy , 2016, Journal of Medical Genetics.

[12]  P. Chiurazzi,et al.  Advances in understanding – genetic basis of intellectual disability , 2016, F1000Research.

[13]  M. Mann,et al.  Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA , 2016, Science.

[14]  Senlin Zhao,et al.  Elevated expression of Thoc1 is associated with aggressive phenotype and poor prognosis in colorectal cancer. , 2015, Biochemical and biophysical research communications.

[15]  G. Superti-Furga,et al.  Gene essentiality and synthetic lethality in haploid human cells , 2015, Science.

[16]  James Y. Zou.  Analysis of protein-coding genetic variation in 60,706 humans , 2015, Nature.

[17]  L. Vissers,et al.  Genetic studies in intellectual disability and related disorders , 2015, Nature Reviews Genetics.

[18]  C. Schwartz.  X‐Linked Intellectual Disability Genetics , 2015 .

[19]  D. Milani,et al.  Genetic Advances in Intellectual Disability , 2015, Journal of Pediatric Genetics.

[20]  Yongwook Choi,et al.  PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels , 2015, Bioinform..

[21]  B. V. van Bon,et al.  THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability. , 2015, American journal of human genetics.

[22]  Michael J Parker,et al.  Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling. , 2015, American journal of human genetics.

[23]  Bale,et al.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology , 2015, Genetics in Medicine.

[24]  Stuart A. Wilson,et al.  Luzp4 defines a new mRNA export pathway in cancer cells , 2015, Nucleic acids research.

[25]  G. von Heijne,et al.  Tissue-based map of the human proteome , 2015, Science.

[26]  C. Morrison,et al.  The Thoc1 ribonucleoprotein and prostate cancer progression. , 2014, Journal of the National Cancer Institute.

[27]  Kali T. Witherspoon,et al.  Refining analyses of copy number variation identifies specific genes associated with developmental delay , 2014, Nature Genetics.

[28]  D. Wieczorek,et al.  Females with de novo aberrations in PHF6: Clinical overlap of Borjeson–Forssman–Lehmann with Coffin–Siris syndrome , 2014, American journal of medical genetics. Part C, Seminars in medical genetics.

[29]  Stephan J Sanders,et al.  A framework for the interpretation of de novo mutation in human disease , 2014, Nature Genetics.

[30]  A. Need,et al.  One gene, many neuropsychiatric disorders: lessons from Mendelian diseases , 2014, Nature Neuroscience.

[31]  J. Shendure,et al.  A general framework for estimating the relative pathogenicity of human genetic variants , 2014, Nature Genetics.

[32]  K. Hochedlinger,et al.  The THO complex regulates pluripotency gene mRNA export and controls embryonic stem cell self-renewal and somatic cell reprogramming. , 2013, Cell stem cell.

[33]  Michael R. Johnson,et al.  De novo mutations in the classic epileptic encephalopathies , 2013, Nature.

[34]  F. Tempia,et al.  A de novo X;8 translocation creates a PTK2-THOC2 gene fusion with THOC2 expression knockdown in a patient with psychomotor retardation and congenital cerebellar hypoplasia , 2013, Journal of Medical Genetics.

[35]  D. Morgan.  The D box meets its match. , 2013, Molecular cell.

[36]  C. Schwartz,et al.  Intellectual disability associated with a homozygous missense mutation in THOC6 , 2013, Orphanet Journal of Rare Diseases.

[37]  Rune Matthiesen,et al.  Integrative analysis of the ubiquitin proteome isolated using Tandem Ubiquitin Binding Entities (TUBEs). , 2012, Journal of proteomics.

[38]  Jorge Cuéllar,et al.  Architecture and nucleic acids recognition mechanism of the THO complex, an mRNP assembly factor , 2012, The EMBO journal.

[39]  Edward L. Huttlin,et al.  Systematic and quantitative assessment of the ubiquitin-modified proteome. , 2011, Molecular cell.

[40]  Sebastian A. Wagner,et al.  A Proteome-wide, Quantitative Survey of In Vivo Ubiquitylation Sites Reveals Widespread Regulatory Roles* , 2011, Molecular & Cellular Proteomics.

[41]  T. Tamura,et al.  Identification of mRNAs that are spliced but not exported to the cytoplasm in the absence of THOC5 in mouse embryo fibroblasts. , 2011, RNA.

[42]  J. Groothoff,et al.  Prevalence of chronic health conditions in children with intellectual disability: a systematic literature review. , 2011, Intellectual and developmental disabilities.

[43]  S. Masuda,et al.  The Closely Related RNA helicases, UAP56 and URH49, Preferentially Form Distinct mRNA Export Machineries and Coordinately Regulate Mitotic Progression , 2010, Molecular biology of the cell.

[44]  Anthony D Whetton,et al.  THOC5/FMIP, an mRNA export TREX complex protein, is essential for hematopoietic primitive cell survival in vivo , 2010, BMC Biology.

[45]  D. Geschwind,et al.  Functional and Evolutionary Insights into Human Brain Development through Global Transcriptome Analysis , 2009, Neuron.

[46]  Jianmin Wang,et al.  Thoc1 Deficiency Compromises Gene Expression Necessary for Normal Testis Development in the Mouse , 2009, Molecular and Cellular Biology.

[47]  Ed Hurt,et al.  Adaptor Aly and co‐adaptor Thoc5 function in the Tap‐p15‐mediated nuclear export of HSP70 mRNA , 2009, The EMBO journal.

[48]  H. Kimura,et al.  MKKS is a centrosome-shuttling protein degraded by disease-causing mutations via CHIP-mediated ubiquitination. , 2007, Molecular biology of the cell.

[49]  M. Mann,et al.  Global, In Vivo, and Site-Specific Phosphorylation Dynamics in Signaling Networks , 2006, Cell.

[50]  Xiaoling Wang,et al.  Thoc1/Hpr1/p84 Is Essential for Early Embryonic Development in the Mouse , 2006, Molecular and Cellular Biology.

[51]  Nancy Hopkins,et al.  Identification of 315 genes essential for early zebrafish development. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[52]  T. Köcher,et al.  Genome-wide analysis of mRNAs regulated by the THO complex in Drosophila melanogaster , 2004, Nature Structural &Molecular Biology.

[53]  R. Hussain,et al.  The influence of intellectual disability on life expectancy. , 2002, The journals of gerontology. Series A, Biological sciences and medical sciences.

[54]  Kinji Ohno,et al.  Rules and tools to predict the splicing effects of exonic and intronic mutations , 2018, Wiley interdisciplinary reviews. RNA.

[55]  G. Hautbergue,et al.  RNA Nuclear Export: From Neurological Disorders to Cancer. , 2017, Advances in experimental medicine and biology.

[56]  H. Ropers,et al.  X-linked mental retardation , 2005, Nature Reviews Genetics.