Impaired protein hydroxylase activity causes replication stress and developmental abnormalities in humans

Although protein hydroxylation is a relatively poorly characterized posttranslational modification, it has received significant recent attention following seminal work uncovering its role in oxygen sensing and hypoxia biology. Although the fundamental importance of protein hydroxylases in biology is becoming clear, the biochemical targets and cellular functions often remain enigmatic. JMJD5 is a JmjC-only protein hydroxylase that is essential for murine embryonic development and viability. However, no germline variants in JmjC-only hydroxylases, including JMJD5, have yet been described that are associated with any human pathology. Here we demonstrate that biallelic germline JMJD5 pathogenic variants are deleterious to JMJD5 mRNA splicing, protein stability, and hydroxylase activity, resulting in a human developmental disorder characterized by severe failure to thrive, intellectual disability, and facial dysmorphism. We show that the underlying cellular phenotype is associated with increased DNA replication stress and that this is critically dependent on the protein hydroxylase activity of JMJD5. This work contributes to our growing understanding of the role and importance of protein hydroxylases in human development and disease.

Automated summary

Although protein hydroxylation is not well understood, recent research has revealed its role in oxygen sensing and hypoxia biology. JMJD5, a protein hydroxylase essential for mouse embryonic development and viability, has been found to have pathogenic variants that cause severe developmental disorders in humans. These variants affect mRNA splicing, protein stability, and hydroxylase activity, leading to failure to thrive, intellectual disability, and facial dysmorphism. This study contributes to our understanding of the importance of protein hydroxylases in human development and disease.