Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis

Abstract

MATR3 is an RNA- and DNA-binding protein that interacts with TDP-43, a disease protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Using exome sequencing, we identified mutations in MATR3 in ALS kindreds. We also observed MATR3 pathology in ALS-affected spinal cords with and without MATR3 mutations. Our data provide more evidence supporting the role of aberrant RNA processing in motor neuron degeneration.

Figure 1. Pedigrees of patients with MATR3 mutations

Mutant alleles are indicated by mt, whereas wild-type alleles are indicated by wt. Genotypes of presumed obligate carriers are in brackets. Red asterisks indicate individuals who underwent clinical examination.

Figure 2. Lumbar spinal cord tissue immunostained for MATR3 and counterstained with hemotoxylin

(a) Control spinal cord exhibits MATR3 nuclear immunoreactivity in some motor neurons, with weak glial cell immunostaining. (b) ALS cases exhibit strong nuclear immunoreactivity with cytoplasmic immunoreactivity present in some motor neurons either diffusely or in cytoplasmic puncta. Strong glial immunostaining is also noted in ALS patients. (c) Patient with the p.Phe115Cys MATR3 mutation exhibits strong nuclear staining, as well as cytoplasmic staining in many cells. Images are taken at 20× magnification and insets are at 40× magnification. Scale bars represent 50um.

Figure 3. Immunoprecipitation of MATR3 with TDP-43

(a) FLAG-MATR3 was expressed in HEK293FT cells, immunoprecipitated using anti-FLAG antibody, and probed with TDP-43 and DHX9 antibodies. (b) Graphs show mean +/− SEM based on 10 replicate immunoprecipitation experiments. Differences in interaction between MATR3 and TDP-43 were tested with Wilcoxon signed rank test (**p<0.01).