Clinical and functional characterization of recurrent missense variants implicated in<i>THOC6</i>-related intellectual disability

Mattioli, Francesca; Isidor, Bertrand; Abdul‐Rahman, Omar; Gunter, Andrew T.; Huang, Lijia; Kumar, Raman; Beaulieu, Chandree L.; Gécz, Jozef; Innes, A. Micheil; Mandel, Jean Louis; Piton, Amélie

doi:10.1093/hmg/ddy391

Cited by 22 publications

(33 citation statements)

References 31 publications

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“…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. We and others have presented evidence showing that perturbed mRNA export leads to altered cellular function, thus causing a range of diseases (Di Gregorio et al, 2013;Kumar et al, 2015Kumar et al, , 2018Heath et al, 2016;Mattioli et al, 2019). During the last few years, we have focussed on the association of variation in the THOC2 gene and NDDs.…”

Section: Discussionmentioning

confidence: 99%

“…Variants in TREX subunit proteins can alter their stability (Kumar et al, 2015(Kumar et al, , 2018; e.g., THOC2 ID variants), interaction (e.g., THOC6 syndromic ID variants; Mattioli et al, 2019) and/or localization (e.g., THOC6 syndromic ID variants; Mattioli et al, 2019). We observed reduced levels of p.Arg77Cys THOC2 (although the stability of this variant exogenously expressed in HEK293T cells was uninformative, see Figure 3 in Kumar et al, 2018) and p.Tyr881Cys THOC2 in the affected LCLs and p.Asn666Asp THOC2 affected fibroblasts (without THOC2 mislocalization).…”

Section: Discussionmentioning

confidence: 99%

“…One such pathway-that has been the focus of our ongoing investigations-is of the highly conserved TREX (TRanscription-EXport) mRNA export pathway. Multiple TREX complex subunits (e.g., THOC1, THOC2, THOC5, THOC6, and THOC7) have been implicated in NDDs and human disease (Kumar et al, 2015(Kumar et al, , 2018Heath et al, 2016;Amos et al, 2017;Mattioli et al, 2019). TREX-mediated mRNA export from the nucleus to the cytoplasm is a complex and highly conserved pathway in all eukaryotes.…”

Section: Introductionmentioning

confidence: 99%

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

Kumar

Palmer

Gardner

et al. 2020

Front. Mol. Neurosci.

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Kumar

Palmer

Gardner

et al. 2020

Front. Mol. Neurosci.

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“…Targeted sequencing of hundred candidate genes for ID did not reveal pathogenic variants 29 . A family trio-based WES was performed as previously described 30…”

Section: Patients and Genetic Analysesmentioning

confidence: 99%

“…To control transfection efficiency, cells were co-transfected using a previously published pcDNA3.1-FLAG-THOC6 constructs. 30 . HeLa cells were lysed in RIPA buffer with protease inhibitor cocktail (Roche) 24h hours after transfection.…”

Section: Western Blot and Immunofluorescencementioning

confidence: 99%

Highly clustered de novo frameshift variants in the neuronal splicing factor NOVA2 result in a specific abnormal C terminal part and cause a severe form of intellectual disability with autistic features

Mattioli

Hayot

Drouot

et al. 2019

Preprint

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The Neuro-Oncological Ventral Antigen 2 NOVA2 protein is a major factor regulating neuron specific alternative splicing, previously associated with an acquired neurologic condition, the paraneoplastic opsoclonus-myoclonus ataxia (POMA). We report here six individuals with de novo frameshift variants in the NOVA2 gene affected with a severe neurodevelopmental disorder characterized by intellectual disability (ID), motor and speech delay, autistic features, hypotonia, feeding difficulties, spasticity or ataxic gait and abnormal brain MRI. The six variants lead to the same reading frame, adding a common 133 aa long proline rich C-terminus part instead of the last KH RNA binding domain. We detected fortyone genes differentially spliced after NOVA2 inactivation in human neural cells. The mutant NOVA2 protein shows decreased ability to bind a target RNA, to regulate specific splicing events and to rescue the phenotype of altered retinotectal axonal pathfinding induced by loss of NOVA2 ortholog in zebrafish. Our results suggest a partial loss-of-function mechanism rather than a full heterozygous loss of function, although a specific contribution of the novel C terminal extension cannot be excluded on the basis of the genetic findings.

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A truncating variant in the THOC6 gene with new findings in a patient with Beaulieu‐Boycott‐Innes syndrome

Kiraz

Tubaş

Seber

2022

American J of Med Genetics Pt A

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Beaulieu‐Boycott‐Innes syndrome (BBIS; MIM#613680) is a rare, autosomal recessive neurodevelopmental genetic disorder associated with pathogenic variants in the THOC6 gene (*615403). Intellectual disability, dysmorphic facial features, developmental delay, structural cardiac and genitourinary anomalies, and dental caries are suggestive findings of the syndrome. Exome sequencing (ES) may facilitate the diagnosis of this syndrome, whose clinical features can be nonspecific. Here we report a BBIS patient with a homozygous truncating variant (NM_024339.5:c.299G>A; p.Trp100Ter) in the THOC6 gene, diagnosed by ES analysis. The patient's variant is novel and some features such as clivus dysplasia, occult spina bifida, tapered fingers, and upturned fleshy earlobes have not been reported in the literature before. This new case report will expand the knowledge of BBIS and provide more information about the genetic variants and phenotypic spectrum. Also, new cases with THOC6 variants will define the core clinical features and common phenotypes of the BBIS over time.

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Clinical and functional characterization of recurrent missense variants implicated inTHOC6-related intellectual disability

Cited by 22 publications

References 31 publications

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

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

Highly clustered de novo frameshift variants in the neuronal splicing factor NOVA2 result in a specific abnormal C terminal part and cause a severe form of intellectual disability with autistic features

A truncating variant in the THOC6 gene with new findings in a patient with Beaulieu‐Boycott‐Innes syndrome

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