Bi-allelic PRMT9 loss-of-function variants cause a syndromic form of intellectual disability.

Protein arginine methyltransferase 9 (PRMT9) is part of the PRMT family, and it is suspected to function in pathways relevant to neurodevelopment. It is thought to participate in alternative splicing through interactions with the splicing factor SF3B2 (SAP145). In this study, we report 26 families (...

Descripción completa

Detalles Bibliográficos
Autores: Kröll-Hermi A, Stoetzel C, Etard C, Halabelian L, Schaefer E, Scheidecker S, Kahrizi K, Payman J, Geoffroy V, Prasad M, Obringer C, Ruch L, Girard A, Zeng H, Li F, Plassard D, Keime C, Mattioli F, Feger C, Piton A, Fujita A, Matsumoto N, Castro MAA, Ae KC, Ruaud L, Levy J, Dozières B, Tabet AC, Wentzensen IM, Santiago-Sim T, Yusupov R, Tveten K, Smeland MF, Alkhunaizi E, Cowing G, Li C, Wortmann SB, Feichtinger RG, Mayr JA, Gonorazky H, Jing G, Wang X, Wang J, Bierhals T, Grinstein L, Herget T, Ruiz A, Gabau E, Kampmeier A, Kassel O, Kuechler A, Platzer K, Jamra RA, Woerner A, Idleburg M, Kircher SG, Laccone F, Golob B, Peterlin B, Cuturilo G, Tasic V, Kolvenbach CM, Hildebrandt F, Ramos LLP, Kok F, Buck CB, van de Laar IMBH, de Man SA, Tasdelen E, Sezer A, Büke A, Yavuz Z, Çomoglu SS, Costin C, Tran Mau Them F, Lacaze E, Courtin T, Héron D, Keren B, Whalen S, Roume J, Yang Y, Hoffer MJV, van Haeringen A, Najmabadi H, Arrowsmith CH, Strähle U, Dollfus H, Muller J
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Institut d'Investigació i Innovació Parc Taulí (I3PT)
Repositorio:r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
OAI Identifier:oai:i3pt.fundanetsuite.com:p6831
Acceso en línea:https://i3pt.portalinvestigacion.com/publicaciones/6831
https://www.scopus.com/inward/record.uri?eid=2-s2.0-105023389271&doi=10.1016%2Fj.ajhg.2025.10.014&partnerID=40&md5=0bedf5d385d1a81fb87ddb9beccb1412
Access Level:acceso abierto
Palabra clave:PRMT9, intellectual disability, neurodevelopmental disorder, primary cilium, whole-exome sequencing, zebrafish
Descripción
Sumario:Protein arginine methyltransferase 9 (PRMT9) is part of the PRMT family, and it is suspected to function in pathways relevant to neurodevelopment. It is thought to participate in alternative splicing through interactions with the splicing factor SF3B2 (SAP145). In this study, we report 26 families (35 individuals) with bi-allelic loss-of-function variants in PRMT9, implicating PRMT9 in an autosomal-recessive human disease. Individuals primarily present with a neurodevelopmental disorder characterized by global developmental delay, learning disabilities, mild to severe intellectual disability, autism spectrum disorder, epilepsy, and hypotonia. The mutation spectrum includes 26 different variants such as frameshifting indels, nonsense variants, missense variants, and two copy-number variants. Mapping of the disease-causing missense variants onto the crystal structure of PRMT9 revealed that several of the variants reside within the catalytically active module of PRMT9, likely impairing its methyltransferase activity and resulting in a loss of function. In skin fibroblasts derived from affected individuals, we observed reduced expression at the RNA and/or protein level and subsequent aberrant methylation activity. Moreover, transcriptomic analysis of fibroblasts from affected individuals indicated differential expression of genes related to intellectual disability, autism, and cilia, suggesting a role of PRMT9 during ciliogenesis. Under ciliogenesis conditions, the skin-derived fibroblasts exhibited anomalies in the length of primary cilia but normal amounts of cilia. In addition, a prmt9 knockout zebrafish model displayed abnormal social preference in adult animals. Altogether, our findings implicate bi-allelic PRMT9 loss-of-function variants as causal for neurodevelopmental disorders.

Similares en LA Referencia