Document Type
Article
Publication Date
2-22-2024
Original Citation
Werren E,
LaForce G,
Srivastava A,
Perillo D,
Li S,
Johnson K,
Baris S,
Berger B,
Regan S,
Pfennig C,
de Munnik S,
Pfundt R,
Hebbar M,
Jimenez-Heredia R,
Karakoc-Aydiner E,
Ozen A,
Dmytrus J,
Krolo A,
Corning K,
Prijoles E,
Louie R,
Lebel R,
Le T,
Amiel J,
Gordon C,
Boztug K,
Girisha K,
Shukla A,
Bielas S,
Schaffer A.
TREX tetramer disruption alters RNA processing necessary for corticogenesis in THOC6 Intellectual Disability Syndrome. Nat Commun. 2024;15(1):1640.
Keywords
JGM, Humans, Animals, Mice, RNA, Intellectual Disability, RNA, Messenger, RNA Processing, Post-Transcriptional, RNA Transport, Mammals, Nuclear Proteins, RNA-Binding Proteins, Stilbenes, Sulfonic Acids
JAX Source
Nat Commun. 2024;15(1):1640.
ISSN
2041-1723
PMID
38388531
Grant
Leakey Foundation Dissertation Fieldwork Grant, the University of Michigan Rackham Candidate Research Grant, the Joan B. Kessler Award, and the University of Michigan Pandemic Research Recovery Award to E.A.W
Abstract
THOC6 variants are the genetic basis of autosomal recessive THOC6 Intellectual Disability Syndrome (TIDS). THOC6 is critical for mammalian Transcription Export complex (TREX) tetramer formation, which is composed of four six-subunit THO monomers. The TREX tetramer facilitates mammalian RNA processing, in addition to the nuclear mRNA export functions of the TREX dimer conserved through yeast. Human and mouse TIDS model systems revealed novel THOC6-dependent, species-specific TREX tetramer functions. Germline biallelic Thoc6 loss-of-function (LOF) variants result in mouse embryonic lethality. Biallelic THOC6 LOF variants reduce the binding affinity of ALYREF to THOC5 without affecting the protein expression of TREX members, implicating impaired TREX tetramer formation. Defects in RNA nuclear export functions were not detected in biallelic THOC6 LOF human neural cells. Instead, mis-splicing was detected in human and mouse neural tissue, revealing novel THOC6-mediated TREX coordination of mRNA processing. We demonstrate that THOC6 is required for key signaling pathways known to regulate the transition from proliferative to neurogenic divisions during human corticogenesis. Together, these findings implicate altered RNA processing in the developmental biology of TIDS neuropathology.
Comments
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