Relevance to Autism

Kroll-Hermi et al., 2025 reported 35 individuals from 26 families with biallelic loss-of-function variants in PRMT9 presenting with a neurodevelopmental disorder characterized by global developmental delay, learning disabilities, mild to severe intellectual disability, autism spectrum disorder, epilepsy, and hypotonia; skin fibroblasts from affected individuals exhibited reduced expression at the RNA and/or protein level and subsequent aberrant methylation activity, as well as anomalies in the length of primary cilia under ciliogenesis conditions, while a prmt9 knockout zebrafish model displayed abnormal social preference in adult animals. A de novo loss-of-function variant and a de novo missense variant in PRMT9 had previously been reported in ASD probands from the SPARK cohort (Zhou et al., 2022). Using a Prmt9 conditional knockout (cKO) mouse, Shen et al., 2024 demonstrated that knockout of Prmt9 in hippocampal neurons caused alternative splicing of ~1900 genes, which likely accounted for the aberrant synapse development and impaired learning and memory observed in Prmt9 cKO mice; furthermore, the authors identified a methylation-sensitive protein-RNA interaction between the arginine 508 (R508) of the splicing factor SF3B2, the site that is exclusively methylated by PRMT9, and the pre-mRNA anchoring site, a cis-regulatory element that is critical for RNA splicing.

Molecular Function

This gene encodes a type II methyltransferase. Post-translational modification of target proteins by PRMTs plays an important regulatory role in many biological processes, whereby PRMTs methylate arginine residues by transferring methyl groups from S-adenosyl-L-methionine to the guanidino nitrogen atoms of arginine. The protein encoded by this gene methylates spliceosome associated protein 145 to regulate alternative splicing and acts as a modulator of small nuclear ribonucleoprotein maturation.

External Links

References