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 splicing-defective 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 and 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.
Highlights
Neurodevelopmental disorders (NDDs) caused by genetic, epigenetic and environmental factors are clinically heterogeneous conditions affecting the central nervous system in children and include intellectual disability (ID), epilepsy, autism and cerebral palsy
These variants were identified from either whole exome (WES) or whole-genome sequencing (WGS) of the affected individuals and confirmed by Sanger sequencing of the PCR amplified variant-carrying region from gDNAs of the parents and the affected individuals
TREX-mediated mRNA export is a fundamental process that is essential for the export of mRNA from the cytoplasm to the nucleus to allow translation of the normal level of protein required for efficient growth and development
Summary
Neurodevelopmental disorders (NDDs) caused by genetic, epigenetic and environmental factors are clinically heterogeneous conditions affecting the central nervous system in children and include intellectual disability (ID), epilepsy, autism and cerebral palsy. Many molecular causes of NDDs disrupt diverse cellular pathways, affecting neuronal development, proliferation and/or migration of cells to cause learning and behavioral disabilities (Srivastava and Schwartz, 2014). One such pathway—that has been the focus of our ongoing investigations—is of the highly conserved TREX (TRanscriptionEXport) mRNA export pathway. We have previously reported genetic and molecular evidence implicating a large number of missense and splicing-defective variants in THOC2–which codes for the largest subunit of the TREX mRNA export complex—in NDDs (Mental retardation, X-linked 12/35 MIM 300957; Kumar et al, 2015, 2018). We present genetic and molecular evidence on a set of novel THOC2 variants, and using aggregate data, refine the core clinical phenotype of THOC2 NDDs
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