Unknown

Dataset Information

0

Spliceosome malfunction causes neurodevelopmental disorders with overlapping features.


ABSTRACT: Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.

SUBMITTER: Li D 

PROVIDER: S-EPMC10760965 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

altmetric image

Publications

Spliceosome malfunction causes neurodevelopmental disorders with overlapping features.

Li Dong D   Wang Qin Q   Bayat Allan A   Battig Mark R MR   Zhou Yijing Y   Bosch Daniëlle Gm DG   van Haaften Gijs G   Granger Leslie L   Petersen Andrea K AK   Pérez-Jurado Luis A LA   Aznar-Laín Gemma G   Aneja Anushree A   Hancarova Miroslava M   Bendova Sarka S   Schwarz Martin M   Kremlikova Pourova Radka R   Sedlacek Zdenek Z   Keena Beth A BA   March Michael E ME   Hou Cuiping C   O'Connor Nora N   Bhoj Elizabeth J EJ   Harr Margaret H MH   Lemire Gabrielle G   Boycott Kym M KM   Towne Meghan M   Li Megan M   Tarnopolsky Mark M   Brady Lauren L   Parker Michael J MJ   Faghfoury Hanna H   Parsley Lea Kristin LK   Agolini Emanuele E   Dentici Maria Lisa ML   Novelli Antonio A   Wright Meredith M   Palmquist Rachel R   Lai Khanh K   Scala Marcello M   Striano Pasquale P   Iacomino Michele M   Zara Federico F   Cooper Annina A   Maarup Timothy J TJ   Byler Melissa M   Lebel Robert Roger RR   Balci Tugce B TB   Louie Raymond R   Lyons Michael M   Douglas Jessica J   Nowak Catherine C   Afenjar Alexandra A   Hoyer Juliane J   Keren Boris B   Maas Saskia M SM   Motazacker Mahdi M MM   Martinez-Agosto Julian A JA   Rabani Ahna M AM   McCormick Elizabeth M EM   Falk Marni J MJ   Ruggiero Sarah M SM   Helbig Ingo I   Møller Rikke S RS   Tessarollo Lino L   Tomassoni Ardori Francesco F   Palko Mary Ellen ME   Hsieh Tzung-Chien TC   Krawitz Peter M PM   Ganapathi Mythily M   Gelb Bruce D BD   Jobanputra Vaidehi V   Wilson Ashley A   Greally John J   Jacquemont Sébastien S   Jizi Khadijé K   Bruel Ange-Line AL   Quelin Chloé C   Misra Vinod K VK   Chick Erika E   Romano Corrado C   Greco Donatella D   Arena Alessia A   Morleo Manuela M   Nigro Vincenzo V   Seyama Rie R   Uchiyama Yuri Y   Matsumoto Naomichi N   Taira Ryoji R   Tashiro Katsuya K   Sakai Yasunari Y   Yigit Gökhan G   Wollnik Bernd B   Wagner Michael M   Kutsche Barbara B   Hurst Anna Ce AC   Thompson Michelle L ML   Schmidt Ryan R   Randolph Linda L   Spillmann Rebecca C RC   Shashi Vandana V   Higginbotham Edward J EJ   Cordeiro Dawn D   Carnevale Amanda A   Costain Gregory G   Khan Tayyaba T   Funalot Benoît B   Tran Mau-Them Frederic F   Fernandez Garcia Moya Luis L   García-Miñaúr Sixto S   Osmond Matthew M   Chad Lauren L   Quercia Nada N   Carrasco Diana D   Li Chumei C   Sanchez-Valle Amarilis A   Kelley Meghan M   Nizon Mathilde M   Jensson Brynjar O BO   Sulem Patrick P   Stefansson Kari K   Gorokhova Svetlana S   Busa Tiffany T   Rio Marlène M   Hadj Habdallah Hamza H   Lesieur-Sebellin Marion M   Amiel Jeanne J   Pingault Véronique V   Mercier Sandra S   Vincent Marie M   Philippe Christophe C   Fatus-Fauconnier Clemence C   Friend Kathryn K   Halligan Rebecca K RK   Biswas Sunita S   Rosser Jane J   Shoubridge Cheryl C   Corbett Mark M   Barnett Christopher C   Gecz Jozef J   Leppig Kathleen K   Slavotinek Anne A   Marcelis Carlo C   Pfundt Rolph R   de Vries Bert Ba BB   van Slegtenhorst Marjon A MA   Brooks Alice S AS   Cogne Benjamin B   Rambaud Thomas T   Tümer Zeynep Z   Zackai Elaine H EH   Akizu Naiara N   Song Yuanquan Y   Hakonarson Hakon H  

The Journal of clinical investigation 20240102 1


Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 va  ...[more]

Similar Datasets

2023-10-24 | GSE246137 | GEO
2023-10-25 | GSE246135 | GEO
2023-10-25 | GSE246136 | GEO
| PRJNA1031622 | ENA
| PRJNA1031628 | ENA
| PRJNA1031629 | ENA
| S-EPMC8341807 | biostudies-literature
| S-EPMC6731356 | biostudies-literature
| S-EPMC2919953 | biostudies-literature
| S-EPMC4989203 | biostudies-literature