TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis (ALS) have been identified. The study found that mutations in the TARDBP gene, which encodes TDP-43, are associated with ALS. In a family with ALS, a mutation (M337V) in TARDBP was found to segregate with the disease. This mutation was confirmed to be linked to chromosome 1p36, which contains the TARDBP locus. Mutant TDP-43 fragments more readily than wild-type and cause neural apoptosis and developmental delay in chick embryos. These findings suggest a pathophysiological link between TDP-43 and ALS. In addition, a missense mutation (Q331K) was found in a cohort of 200 British sporadic ALS cases. This mutation was found to be 18 base pairs upstream of the familial mutation and predicted to substitute lysine for glutamine. No mutations were detected in 500 British Caucasian controls, emphasizing the high degree of evolutionary conservation. Functional studies showed that mutant TDP-43 proteins caused increased fragmentation and toxicity to neural cells. The study also found that TDP-43 mutations may be pathogenically linked to ALS. The identification of TDP-43 mutations that result in increased fragmentation and toxicity to neural cells strongly supports a pathophysiological role for TDP-43 misaccumulation in ALS. The G294A, Q331K, and M337V mutations are all localized to a highly conserved region of the C-terminus of TDP-43 known to be involved in protein-protein interactions. The Q331K mutation creates a new protein kinase A site, which may result in abnormal phosphorylation. The G294A mutation interrupts a glycine run motif characteristic of all hnRNPs and may interfere with RNA binding and gene suppression. The study also found that TDP-43 is a ubiquitously expressed nuclear protein capable of binding DNA and RNA, which regulates transcription and splicing but may also be involved in microRNA biogenesis, apoptosis and cell division. The accumulation of hyperphosphorylated TDP-43 fragments in the perikaryon of neurons in FTLD-U and ALS is accompanied by a striking loss of TDP-43 from the nucleus. The sequestration of TDP-43 would be predicted to disrupt the regulation of transcription and splicing, which may account for the 1.5 fold increase in TDP-43 mRNA seen in FTLD-U brains.TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis (ALS) have been identified. The study found that mutations in the TARDBP gene, which encodes TDP-43, are associated with ALS. In a family with ALS, a mutation (M337V) in TARDBP was found to segregate with the disease. This mutation was confirmed to be linked to chromosome 1p36, which contains the TARDBP locus. Mutant TDP-43 fragments more readily than wild-type and cause neural apoptosis and developmental delay in chick embryos. These findings suggest a pathophysiological link between TDP-43 and ALS. In addition, a missense mutation (Q331K) was found in a cohort of 200 British sporadic ALS cases. This mutation was found to be 18 base pairs upstream of the familial mutation and predicted to substitute lysine for glutamine. No mutations were detected in 500 British Caucasian controls, emphasizing the high degree of evolutionary conservation. Functional studies showed that mutant TDP-43 proteins caused increased fragmentation and toxicity to neural cells. The study also found that TDP-43 mutations may be pathogenically linked to ALS. The identification of TDP-43 mutations that result in increased fragmentation and toxicity to neural cells strongly supports a pathophysiological role for TDP-43 misaccumulation in ALS. The G294A, Q331K, and M337V mutations are all localized to a highly conserved region of the C-terminus of TDP-43 known to be involved in protein-protein interactions. The Q331K mutation creates a new protein kinase A site, which may result in abnormal phosphorylation. The G294A mutation interrupts a glycine run motif characteristic of all hnRNPs and may interfere with RNA binding and gene suppression. The study also found that TDP-43 is a ubiquitously expressed nuclear protein capable of binding DNA and RNA, which regulates transcription and splicing but may also be involved in microRNA biogenesis, apoptosis and cell division. The accumulation of hyperphosphorylated TDP-43 fragments in the perikaryon of neurons in FTLD-U and ALS is accompanied by a striking loss of TDP-43 from the nucleus. The sequestration of TDP-43 would be predicted to disrupt the regulation of transcription and splicing, which may account for the 1.5 fold increase in TDP-43 mRNA seen in FTLD-U brains.