THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability

Abstract

Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities.

The role of TREX in gene expression and disease

“…THOC2 is the human ortholog of the yeast Tho2 protein and, as the largest subunit of TREX, is proposed to act as a scaffold for the formation of the complex [53]. THOC2 is an essential component for maintaining TREX function in humans [15,42], and mutations in the THOC2 gene are associated with intellectual disabilities [22,54]. The conserved THOC3 (hTEX1) protein has been recently established as a component of the THO subcomplex in TREX and contains WD40 repeat motifs that allow multiple protein interactions (Figure 2) [10,15].…”

“…In the first class, missense mutations in the THOC2 gene cause syndromic intellectual disability [22]. Additionally, a de novo translocation event in the vicinity of THOC2 on the X-chromosome has been described in a child with cerebellar hypoplasia, ataxia and retardation [54].…”

Asymmetric Arginine Dimethylation Modulates Mitochondrial Energy Metabolism and Homeostasis in Caenorhabditis elegans

“…Furthermore, genetic analysis demonstrated that food avoidance of prmt-1 null mutants can be blocked by silencing either thoc-2 or inx-17, both of which have been recently identified as mitochondrial surveillance genes (16). THOC-2 has been shown to be an mRNA-binding protein facilitating the nuclear export of mRNA and required for proper neuronal development (42), while the function of INX-17, which is expressed abundantly in interneurons, is still unknown. Although the detailed mechanisms underlying food avoidance by mitochondrial dysfunction remain unclear, it is possible that the loss of asymmetric arginine dimethylation induces this defensive behavior through the same pathway and neuronal circuits as those induced by inhibition of OXPHOS components (e.g., isp-1), because the stress responses triggered in the two events are similar (30)(31)(32).…”

RNA Degradation in Neurodegenerative Disease

“…Chromosomal translocation and inactivation of THOC2, a subunit of the core TREX complex, leads to cognitive impairment, cerebellar hypoplasia, and congenital ataxia in humans[278]. Additionally, missense mutations in THOC2 have been implicated in fragile X syndrome [279], and mutations in a second THO subunit, THOC6, lead to intellectual disabilities [280]. Moreover, loss of function mutations in Gle1 results in ALS [281] and fetal motor neuron disease [282].…”