TY - JOUR
T1 - TREX tetramer disruption alters RNA processing necessary for corticogenesis in THOC6 Intellectual Disability Syndrome
AU - Werren, Elizabeth A.
AU - LaForce, Geneva R.
AU - Srivastava, Anshika
AU - Perillo, Delia R.
AU - Li, Shaokun
AU - Johnson, Katherine
AU - Baris, Safa
AU - Berger, Brandon
AU - Regan, Samantha L.
AU - Pfennig, Christian D.
AU - de Munnik, Sonja
AU - Pfundt, Rolph
AU - Hebbar, Malavika
AU - Jimenez-Heredia, Raúl
AU - Karakoc-Aydiner, Elif
AU - Ozen, Ahmet
AU - Dmytrus, Jasmin
AU - Krolo, Ana
AU - Corning, Ken
AU - Prijoles, E. J.
AU - Louie, Raymond J.
AU - Lebel, Robert Roger
AU - Le, Thuy Linh
AU - Amiel, Jeanne
AU - Gordon, Christopher T.
AU - Boztug, Kaan
AU - Girisha, Katta M.
AU - Shukla, Anju
AU - Bielas, Stephanie L.
AU - Schaffer, Ashleigh E.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/2/22
Y1 - 2024/2/22
N2 - 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.
AB - 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.
KW - Humans
KW - Animals
KW - Mice
KW - RNA/metabolism
KW - Intellectual Disability/genetics
KW - RNA, Messenger/genetics
KW - RNA Processing, Post-Transcriptional
KW - RNA Transport
KW - Mammals/genetics
KW - Nuclear Proteins/metabolism
KW - RNA-Binding Proteins/genetics
KW - Stilbenes
KW - Sulfonic Acids
UR - http://www.scopus.com/inward/record.url?scp=85185653218&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85185653218&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/bec35cbc-f5dc-3a47-82f5-4cfdb113bbea/
U2 - 10.1038/s41467-024-45948-y
DO - 10.1038/s41467-024-45948-y
M3 - Article
C2 - 38388531
AN - SCOPUS:85185653218
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1640
ER -