Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy.

Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs covalently bound topoisomerase I-DNA complexes and is essential for preventing the formation of double-strand breaks that result when stalled topoisomerase I complexes interfere with DNA replication in yeast. Here we show that a deficiency of this DNA repair pathway in humans does not predispose to neoplasia or dysfunctions in rapidly replicating tissues, but instead causes spinocerebellar ataxia with axonal neuropathy (SCAN1) by affecting large, terminally differentiated, non-dividing neuronal cells. Using genome-wide linkage mapping and a positional candidate approach in a Saudi Arabian family affected with autosomal recessive SCAN1, we identified a homozygous mutation in TDP1 (A1478G) that results in the substitution of histidine 493 with an arginine residue. The His493 residue is conserved in TDP1 across species and is located in the active site of the enzyme. Protein modeling predicts that mutation of this amino acid to arginine will disrupt the symmetric structure of the active site. We propose that loss-of-function mutations in TDP1 may cause SCAN1 either by interfering with DNA transcription or by inducing apoptosis in postmitotic neurons.