Frontotemporal lobar degeneration (FTLD) is the most common cause of early‐onset dementia. Pathological ubiquitinated inclusion bodies observed in FTLD and motor neuron disease (MND) comprise trans‐activating response element (TAR) DNA binding protein (TDP‐43) and/or fused in sarcoma (FUS) protein. Our objective was to identify the causative gene in an FTLD‐MND pedigree with no mutations in known dementia genes.

A mutation screen of candidate genes, luciferase assays, and quantitative polymerase chain reaction (PCR) was performed to identify the biological role of the putative mutation. Neuropathological characterization of affected individuals and western blot studies of cell lines were performed to identify the pathological mechanism of the mutation.

We identified a nonpolymorphic mutation (c.672*51G>T) in the 3′‐untranslated region (UTR) of the Sigma nonopioid intracellular receptor 1 (SIGMAR1) gene in affected individuals from the FTLD‐MND pedigree. The c.672*51G>T mutation increased gene expression by 1.4‐fold, corresponding with a significant 1.5‐fold to 2‐fold change in the SIGMAR1 transcript or Sigma‐1 protein in lymphocyte or brain tissue. Brains of SIGMAR1 mutation carriers displayed a unique pathology with cytoplasmic inclusions immunopositive for either TDP‐43 or FUS but not Sigma‐1. Overexpression of SIGMAR1 shunted TDP‐43 and FUS from the nucleus to the cytoplasm by 2.3‐fold and 5.2‐fold, respectively. Treatment of cells with Sigma‐1 ligands significantly altered translocation of TDP‐43 by up to 2‐fold.

SIGMAR1 is a causative gene for familial FTLD‐MND with a unique neuropathology that differs from other FTLD and MND cases. Our findings also suggest Sigma‐1 drugs as potential treatments for the TDP‐43/FUS proteinopathies. Ann Neurol 2010;68:639–649