Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment

Rudrarup Bhattacharjee; Lachlan A. Jolly; Mark A. Corbett; Ing Chee Wee; Sushma R. Rao; Alison E. Gardner; Tarin Ritchie; Eline J.H. van Hugte; Ummi Ciptasari; Sandra Piltz; Jacqueline E. Noll; Nazzmer Nazri; Clare L. van Eyk; Melissa White; Dani Fornarino; Cathryn Poulton; Gareth Baynam; Lyndsey E. Collins-Praino; Marten F. Snel; Nael Nadif Kasri; Kim M. Hemsley; Paul Q. Thomas; Raman Kumar; Jozef Gecz

doi:10.1038/s41467-024-45121-5

Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment

Rudrarup Bhattacharjee, Lachlan A. Jolly, Mark A. Corbett, Ing Chee Wee, Sushma R. Rao, Alison E. Gardner, Tarin Ritchie, Eline J.H. van Hugte, Ummi Ciptasari, Sandra Piltz, Jacqueline E. Noll, Nazzmer Nazri, Clare L. van Eyk, Melissa White, Dani Fornarino, Cathryn Poulton, Gareth Baynam, Lyndsey E. Collins-Praino, Marten F. Snel, Nael Nadif KasriKim M. Hemsley, Paul Q. Thomas, Raman Kumar, Jozef Gecz

Gene Editing

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

Abstract

We implicated the X-chromosome THOC2 gene, which encodes the largest subunit of the highly-conserved TREX (Transcription-Export) complex, in a clinically complex neurodevelopmental disorder with intellectual disability as the core phenotype. To study the molecular pathology of this essential eukaryotic gene, we generated a mouse model based on a hypomorphic Thoc2 exon 37-38 deletion variant of a patient with ID, speech delay, hypotonia, and microcephaly. The Thoc2 exon 37-38 deletion male (Thoc2Δ/Y) mice recapitulate the core phenotypes of THOC2 syndrome including smaller size and weight, and significant deficits in spatial learning, working memory and sensorimotor functions. The Thoc2Δ/Y mouse brain development is significantly impacted by compromised THOC2/TREX function resulting in R-loop accumulation, DNA damage and consequent cell death. Overall, we suggest that perturbed R-loop homeostasis, in stem cells and/or differentiated cells in mice and the patient, and DNA damage-associated functional alterations are at the root of THOC2 syndrome.

Original language	English
Pages (from-to)	1210
Number of pages	1
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-45121-5
Publication status	Published or Issued - 8 Feb 2024

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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Bhattacharjee, R., Jolly, L. A., Corbett, M. A., Wee, I. C., Rao, S. R., Gardner, A. E., Ritchie, T., van Hugte, E. J. H., Ciptasari, U., Piltz, S., Noll, J. E., Nazri, N., van Eyk, C. L., White, M., Fornarino, D., Poulton, C., Baynam, G., Collins-Praino, L. E., Snel, M. F., ... Gecz, J. (2024). Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment. Nature Communications, 15(1), 1210. https://doi.org/10.1038/s41467-024-45121-5

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title = "Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment",

abstract = "We implicated the X-chromosome THOC2 gene, which encodes the largest subunit of the highly-conserved TREX (Transcription-Export) complex, in a clinically complex neurodevelopmental disorder with intellectual disability as the core phenotype. To study the molecular pathology of this essential eukaryotic gene, we generated a mouse model based on a hypomorphic Thoc2 exon 37-38 deletion variant of a patient with ID, speech delay, hypotonia, and microcephaly. The Thoc2 exon 37-38 deletion male (Thoc2Δ/Y) mice recapitulate the core phenotypes of THOC2 syndrome including smaller size and weight, and significant deficits in spatial learning, working memory and sensorimotor functions. The Thoc2Δ/Y mouse brain development is significantly impacted by compromised THOC2/TREX function resulting in R-loop accumulation, DNA damage and consequent cell death. Overall, we suggest that perturbed R-loop homeostasis, in stem cells and/or differentiated cells in mice and the patient, and DNA damage-associated functional alterations are at the root of THOC2 syndrome.",

author = "Rudrarup Bhattacharjee and Jolly, {Lachlan A.} and Corbett, {Mark A.} and Wee, {Ing Chee} and Rao, {Sushma R.} and Gardner, {Alison E.} and Tarin Ritchie and {van Hugte}, {Eline J.H.} and Ummi Ciptasari and Sandra Piltz and Noll, {Jacqueline E.} and Nazzmer Nazri and {van Eyk}, {Clare L.} and Melissa White and Dani Fornarino and Cathryn Poulton and Gareth Baynam and Collins-Praino, {Lyndsey E.} and Snel, {Marten F.} and {Nadif Kasri}, Nael and Hemsley, {Kim M.} and Thomas, {Paul Q.} and Raman Kumar and Jozef Gecz",

note = "Publisher Copyright: {\textcopyright} 2024. The Author(s).",

year = "2024",

month = feb,

day = "8",

doi = "10.1038/s41467-024-45121-5",

language = "English",

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Bhattacharjee, R, Jolly, LA, Corbett, MA, Wee, IC, Rao, SR, Gardner, AE, Ritchie, T, van Hugte, EJH, Ciptasari, U, Piltz, S, Noll, JE, Nazri, N, van Eyk, CL, White, M, Fornarino, D, Poulton, C, Baynam, G, Collins-Praino, LE, Snel, MF, Nadif Kasri, N, Hemsley, KM, Thomas, PQ, Kumar, R & Gecz, J 2024, 'Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment', Nature Communications, vol. 15, no. 1, pp. 1210. https://doi.org/10.1038/s41467-024-45121-5

TY - JOUR

T1 - Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment

AU - Bhattacharjee, Rudrarup

AU - Jolly, Lachlan A.

AU - Corbett, Mark A.

AU - Wee, Ing Chee

AU - Rao, Sushma R.

AU - Gardner, Alison E.

AU - Ritchie, Tarin

AU - van Hugte, Eline J.H.

AU - Ciptasari, Ummi

AU - Piltz, Sandra

AU - Noll, Jacqueline E.

AU - Nazri, Nazzmer

AU - van Eyk, Clare L.

AU - White, Melissa

AU - Fornarino, Dani

AU - Poulton, Cathryn

AU - Baynam, Gareth

AU - Collins-Praino, Lyndsey E.

AU - Snel, Marten F.

AU - Nadif Kasri, Nael

AU - Hemsley, Kim M.

AU - Thomas, Paul Q.

AU - Kumar, Raman

AU - Gecz, Jozef

PY - 2024/2/8

Y1 - 2024/2/8

N2 - We implicated the X-chromosome THOC2 gene, which encodes the largest subunit of the highly-conserved TREX (Transcription-Export) complex, in a clinically complex neurodevelopmental disorder with intellectual disability as the core phenotype. To study the molecular pathology of this essential eukaryotic gene, we generated a mouse model based on a hypomorphic Thoc2 exon 37-38 deletion variant of a patient with ID, speech delay, hypotonia, and microcephaly. The Thoc2 exon 37-38 deletion male (Thoc2Δ/Y) mice recapitulate the core phenotypes of THOC2 syndrome including smaller size and weight, and significant deficits in spatial learning, working memory and sensorimotor functions. The Thoc2Δ/Y mouse brain development is significantly impacted by compromised THOC2/TREX function resulting in R-loop accumulation, DNA damage and consequent cell death. Overall, we suggest that perturbed R-loop homeostasis, in stem cells and/or differentiated cells in mice and the patient, and DNA damage-associated functional alterations are at the root of THOC2 syndrome.

AB - We implicated the X-chromosome THOC2 gene, which encodes the largest subunit of the highly-conserved TREX (Transcription-Export) complex, in a clinically complex neurodevelopmental disorder with intellectual disability as the core phenotype. To study the molecular pathology of this essential eukaryotic gene, we generated a mouse model based on a hypomorphic Thoc2 exon 37-38 deletion variant of a patient with ID, speech delay, hypotonia, and microcephaly. The Thoc2 exon 37-38 deletion male (Thoc2Δ/Y) mice recapitulate the core phenotypes of THOC2 syndrome including smaller size and weight, and significant deficits in spatial learning, working memory and sensorimotor functions. The Thoc2Δ/Y mouse brain development is significantly impacted by compromised THOC2/TREX function resulting in R-loop accumulation, DNA damage and consequent cell death. Overall, we suggest that perturbed R-loop homeostasis, in stem cells and/or differentiated cells in mice and the patient, and DNA damage-associated functional alterations are at the root of THOC2 syndrome.

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DO - 10.1038/s41467-024-45121-5

M3 - Article

C2 - 38331934

AN - SCOPUS:85184786298

SN - 2041-1723

VL - 15

SP - 1210

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment

Abstract

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