Mechanisms of mRNA processing defects in inherited THOC6 intellectual disability syndrome

• Published in: bioRxiv
• Main Authors: Werren, Elizabeth A, Laforce, Geneva R, Srivastava, Anshika, Perillo, Delia R, Johnson, Katherine, Berger, Brandon, Safa Baris, Regan, Samantha L, Pfennig, Christian D, De Munnik, Sonja, Rolph Pfundt, Hebbar, Malavika, Jimenez-Heredia, Raul, Karakoc-Aydiner, Elif, Ozen, Ahmet, Dmytrus, Jasmin, Krolo, Ana, Corning, Ken, Prijoles, Ej, Louie, Raymond, Lebel, Robert, Le, Thuy-Linh, Gordon, Chris, Girish, Katta M, Boztug, Kaan, Shukla, Anju, Bielas, Stephanie L, Schaffer, Ashleigh E
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 07.09.2022
• Subjects: Intellectual disabilities; Localization; Monomers; mRNA processing; Nuclear transport
• DOI: 10.1101/2022.09.06.506502

THOC6 is the genetic basis of autosomal recessive THOC6 Intellectual Disability Syndrome (TIDS). THOC6 facilitates the formation of the Transcription Export complex (TREX) tetramer, composed of four THO monomers. The TREX tetramer supports mammalian mRNA processing that is distinct from yeast TREX dimer functions. Human and mouse TIDS model systems allow novel THOC6-dependent TREX tetramer functions to be investigated. Biallelic loss-of-function (LOF) THOC6 variants do not influence the expression and localization of TREX members in human cells, but our data suggests reduced binding affinity of ALYREF. Impairment of TREX nuclear export functions were not detected in cells with biallelic THOC6 LOF. Instead, mRNA mis-splicing was observed in human and mouse neural tissue, revealing novel insights into THOC6-mediated TREX coordination of mRNA processing. We demonstrate that THOC6 is required for regulation of key signaling pathways in human corticogenesis that dictate the transition from proliferative to neurogenic divisions that may inform TIDS neuropathology. Competing Interest Statement The authors have declared no competing interest.