The Insertion of an ATTTC Repeat in an Alu Element Hyperactivates a Primate-Specific Neurodevelopmental Enhancer in Spinocerebellar Ataxia Type 37

Alu are evolutionarily very old primate-specific interspersed repeat elements that constitute ∼11% of the human genome. They are a source of short tandem repeats (STRs), which often expand in size and originate inherited neuromuscular and neurodegenerative disorders. How expanded STR insertion mutations within Alu STRs culminate in disease remains unknown. Here we report an Alu STR located in an intron ofDAB1that functions as a neurodevelopmental enhancer. We demonstrated that an ATTTC repeat insertion in thisDAB1Alu STR, known to cause spinocerebellar ataxia type 37 (SCA37), hyperactivates a neurodevelopmentalDAB1enhancer. Importantly, we showed that neurons derived from SCA37 subjects have higher levels ofDAB1expression and DAB1 overexpression causes abnormal axonal pathfindingin vivo. Overall, these results establish that neuronal dysregulation of a developmentalDAB1Alu STR enhancer contributes to SCA37 pathogenesis, an unexplored mechanism likely acting in many Alu STR diseases, potentially reshaping the therapeutic landscape.