TDP-43 A315T mutation in familial motor neuron disease

Abstract

To identify novel causes of familial neurodegenerative diseases, we extended our previous studies of TAR DNA-binding protein 43 (TDP-43) proteinopathies to investigate TDP-43 as a candidate gene in familial cases of motor neuron disease. Sequencing of the TDP-43 gene led to the identification of a novel missense mutation, Ala-315-Thr, which segregates with all affected members of an autosomal dominant motor neuron disease family. The mutation was not found in 1,505 healthy control subjects. The discovery of a missense mutation in TDP-43 in a family with dominantly inherited motor neuron disease provides evidence of a direct link between altered TDP-43 function and neurodegeneration.

Fig

TDP-43 missense mutation A315T within a highly conserved region of exon 6 segregates with all affected members of an autosomal dominant motor neuron disease (MND) family. (A) TAR DNA-binding protein 43 (TDP-43) genomic structure, position of missense mutation, and location of amino acid change adjacent to glycine-rich domain. (B) TDP-43 protein (291-340 amino acids) displays high similarity between species. Residues underlined indicate differences when compared with humans. TDP-43 A315T location is indicated in red. (C) Chromatogram of exon 6 displays a base-pair change (c.1077 G>A) compared with family control. (D) Pedigree of family displays segregation of the mutation with disease (open symbols denote unaffected; closed symbols denote affected with mutation; diagonal line denotes deceased). RsaI restriction digest was used to screen family members and 1,505 control subjects. Direct sequencing was also performed on all family members in this study to verify the mutation.