TREX tetramer disruption alters RNA processing necessary for corticogenesis in THOC6 Intellectual Disability Syndrome

Author:

Werren Elizabeth A.ORCID,LaForce Geneva R.ORCID,Srivastava Anshika,Perillo Delia R.,Li Shaokun,Johnson Katherine,Baris Safa,Berger Brandon,Regan Samantha L.,Pfennig Christian D.,de Munnik Sonja,Pfundt Rolph,Hebbar Malavika,Jimenez-Heredia Raúl,Karakoc-Aydiner Elif,Ozen Ahmet,Dmytrus Jasmin,Krolo Ana,Corning Ken,Prijoles E. J.,Louie Raymond J.,Lebel Robert Roger,Le Thuy-Linh,Amiel Jeanne,Gordon Christopher T.ORCID,Boztug Kaan,Girisha Katta M.ORCID,Shukla AnjuORCID,Bielas Stephanie L.ORCID,Schaffer Ashleigh E.ORCID

Abstract

AbstractTHOC6 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.

Funder

U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development

Publisher

Springer Science and Business Media LLC

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