Expanding Clinical Presentations Due to Variations in THOC2 mRNA Nuclear Export Factor

Abstract

Multiple TREX mRNA export complex subunits (e.g., THOC1, THOC2, THOC5, THOC6, THOC7) have now been implicated in neurodevelopmental disorders (NDDs), neurodegeneration and cancer. We previously implicated missense and splicingdefective THOC2 variants in NDDs and a broad range of other clinical features. Here we report 10 individuals from nine families with rare missense THOC2 variants including the first case of a recurrent variant (p.Arg77Cys), and an additional individual with an intragenic THOC2 microdeletion (Del-Ex37-38). Ex vivo missense variant testing and patient-derived cell line data from current and published studies show 9 of the 14 missense THOC2 variants result in reduced protein stability. The splicing-defective Frontiers in Molecular Neuroscience | www.frontiersin.org February 2020 | Volume 13 | Article 12 Kumar et al. New THOC2 Variants in NDDsand deletion variants result in a loss of small regions of the C-terminal THOC2 RNA binding domain (RBD). Interestingly, reduced stability of THOC2 variant proteins has a flow-on effect on the stability of the multi-protein TREX complex; specifically on the other NDD-associated THOC subunits. Our current, expanded cohort refines the core phenotype of THOC2 NDDs to language disorder and/or ID, with a variable severity, and disorders of growth. A subset of affected individuals' has severe-profound ID, persistent hypotonia and respiratory abnormalities. Further investigations to elucidate the pathophysiological basis for this severe phenotype are warranted.

Structure of the human core transcription-export complex reveals a hub for multivalent interactions

“… ( a ) Recombinant human THO (top), THO ∆THOC6 (middle), THOC1/2/3 (bottom) complex migration in sucrose density gradients (SDS-PAGE stained with Coomassie blue) indicates an oligomeric state consistent with tetramer, dimer, and monomer architectures, respectively. ( b ) Location of human disease-associated mutations in THOC2 ( Kumar et al, 2020 ; Kumar et al, 2018 ; Kumar et al, 2015 ) and THOC6 ( FORGE Canada Consortium et al, 2013 ; Casey et al, 2016 ; Anazi et al, 2016 ; Care4Rare Canada Consortium et al, 2017 ; Mattioli et al, 2019 ). Several THOC6 mutations were shown to affect its stability and lead to the loss of interaction with THO subunits ( Mattioli et al, 2019 ), suggesting that stabilization of the THO tetramer is needed for its full activity.…”

“…b. Location of human disease-associated mutations in THOC2 (Kumar et al, 2020(Kumar et al, , 2018(Kumar et al, , 2015) and THOC6 (Beaulieu et al, 2013;Casey et al, 2016;Anazi et al, 2016;Amos et al, 2017;Mattioli et al, 2019). Several THOC6 mutations were shown to affect its stability and lead to the loss of interaction with THO subunits (Mattioli et al, 2019), suggesting that stabilization of the THO tetramer is needed for its full activity.…”

Integrated Analysis of the Roles of RNA Binding Proteins and Their Prognostic Value in Clear Cell Renal Cell Carcinoma

“…NOVA2 as an AS factor [ 87 ] has been confirmed that it may participate in the occurrence of breast cancer by promoting epithelial-mesenchymal transition [ 88 ]. In addition, studies have shown that THOC6 is related to cancer [ 89 , 90 ].…”

Novel Consensus Splice Site Pathogenic Variation in THOC2 Gene Leads to Recurrent Arthrogryposis Multiplex Congenita Phenotype: A Case Report

“…A search in PubMed using the keyword “ THOC2 ” led to a list of only 17 papers. A total of three seminal papers by Kumar et al have a clinical and genetic characterization of families with THOC2 gene mutations [ 7 , 8 , 9 ]. The findings in these papers have been summarized in Table 2 .…”