De novo truncation variants in the low-complexity C-terminal region of XRN1 are associated with a dominant form of lethal infantile mitochondrial cardiomyopathy

Abstract

XRN1 encodes a highly conserved cytoplasmic 5-3 exoribonuclease involved in mRNA decay and quality control. It localizes to transient ribonucleoprotein aggregates, P-bodies and stress granules, where it interacts with other mRNA decay proteins and is involved in various cellular responses, including an emerging role in viral infection responses. Complete knockout of XRN1 in multicellular organisms is lethal, most likely due to its central role in mRNA homeostasis, with no prior human disease association reported. Here, we characterize seven individuals from six unrelated families with a lethal infantile form of mitochondrial cardiomyopathy caused by heterozygous de novo frameshift truncation variants clustering in the C-terminal region of XRN1, each predicted to evade nonsense-mediated mRNA decay. Each variant results in a near-identical XRN1 C-terminal sequence predicted to alter a characterized binding domain that interacts with the mRNA decapping enhancer EDC4. Biochemical investigations of striated muscle revealed combined oxidative phosphorylation deficiencies, demonstrated by decreased respiratory chain enzyme activities, decreased proteomics abundances, and abnormal histochemical reactivities. Despite having no established mitochondrial function in mammals, clinical and molecular findings across the cohort were consistent with mitochondrial disease. The precise mechanism by which the altered XRN1 proteins cause disease remains to be elucidated.