Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that causes loss of motor neurons. A pathological hallmark of ALS is the presence of ubiquitinated TAR DNA binding protein (TDP-43) inclusions in the cytoplasm of affected cells. Rare pathogenic mutations within the gene TARDBP that encode TDP-43 were recently reported in ALS but their functional consequences are unknown. To further investigate the pathogenic role of TDP-43 in ALS, a mutation analysis of TARDBP was performed in an Australian cohort of 74 sporadic and 30 familial ALS cases. A novel familial ALS mutation in TDP-43 was identified that substitutes a highly conserved residue (G294V) and is predicted to disrupt the glycine rich domain in the C terminus, a region that plays a role in RNA binding and is required for the exon skipping activity of TDP-43.
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K L Williams and J C Durnall contributed equally to this work.
Funding This study was supported by the Peter Stearne grant for familial MND from the Motor Neurone Disease Research Institute of Australia, the Stephen Buckley motor neuron disease research grant from the Australian Rotary Health Research Fund and an NHMRC Career Development Award to IPB.
Competing interests None.
Ethics approval The study was approved by the human research ethics committee of the Sydney South West Area Health Service.
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