Loss ofYthdf3causes Danon disease-like features

YTH domain-containing family (YTHDF1/2/3) recognizes m6A modified mRNAs and regulates their stability, translation and function. We found loss ofYthdf3in mice caused cardiac hypotrophy, myopathy, and intellectual abnormalities, resembling the clinical features of a rare inherited X-linked disorder Danon disease (DD). Mechanistically, this was attributable to the compromised mRNA decay of sex-determining region Y (SRY)-box 9 (Sox9), mediated by YTHDF3 m6A reader function. Targeted therapy with AAV-shRNA againstSox9ameliorated fibrosis, increased neuron number, and significantly improved heart and brain function inYthdf3^−/−mice. Our data reveal that loss of murineYthdf3recapitulates systemic DD-like features, attributable to impairedSox9decay, and highlight a novel therapeutic target for DD.