Global splicing defects caused by chronic low levels of SMN in SMA may be a cause of splicing inefficiency of SETX pre-mRNA resulting in reduced full-length SETX transcripts, thus explaining the low levels of the SETX protein.139-142 A decrease in SETX levels causes accumulation of R-loops and DNA damage in SMA patient fibroblasts and spinal cord motor neurons derived from SMA mice.61 Here, SMN1 is linked to proximal spinal muscular atrophy.