Investigation of the Disease Manifestations and Genetics of a novel TDP1 Mutation, the gene implicated in Spinocerebellar Ataxia with Axonal Neuropathy 1 (SCAN1)

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Janes, Alvin
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Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a protein best-characterized in its DNA repair role via resolution of stalled Topoisomerase1-DNA (TOP1-DNA) complexes. These stalled complexes would otherwise collide with DNA replication machinery and cause DNA damage. Homozygous mutation of TDP1 (H493R) can result in spinocerebellar ataxia with axonal neuropathy (SCAN1, an autosomal recessive neurodegenerative syndrome characterized by early onset cerebellar ataxia that has been so far only characterized in one Saudi Arabian Family. Recently, a novel TDP1 mutation has been found in an American patient, who has a SCAN1-like ataxic phenotype. Differences between this new phenotype and SCAN1 include later onset, potentially a predisposition to tumorigenesis, and an apparent autosomal dominant inheritance pattern. The patient has one wild-type TDP1 allele, and a point mutation in exon 4: 560-1G->A in the other TDP1 allele. The patient's mother had poor balance while walking, and the patient's son was afflicted by two tumours, the latter one claiming his life at age 33. B lymphoblastoid cell lines were generated from the patient (PROP), the patient's daughter (DAU), and the patient's brother (BRO), for further investigation. Western blot analysis showed ~70% decreased baseline expression of TDP1. Comet assay with Topotecan treatment showed no increased DNA damage in PROP/DAU/BRO cells compared to control wild-type cells, unlike SCAN1 cells which showed increased DNA damage. Topotecan is an anticancer drug that stalls TOP1-DNA complexes; defective TDP1 in SCAN1 is unable to resolve the stall, and replication machinery causes DNA damage. This suggests that PROP/DAU/BRO cells have functioning TDP1.
TDP1 Mutation