Heterozygous R1101K mutation of the DCTN1 gene in a family with amyotrophic lateral sclerosis and frontotemporal dementia

The molecular mechanisms underlying the co-occurrence of ALS and FTD remain incompletely understood. We report a heterozygous R1101K mutation of the p150 subunit of the molecular motor dynactin (DCTN1) in a family with amyotrophic lateral sclerosis (ALS) and co-occurrence of frontotemporal dementia (FTD). Three members of our kindred were affected with motor neuron disease and two with dementia in an autosomal dominant pattern of inheritance. We excluded the involvement of the ALS and FTD-linked genes for copper/zinc superoxide dismutase (SOD1) and tau. The present study shows that mutations in DCTN1 may result in a wider range of phenotypes than has been previously appreciated. In this case, mutations in DCTN1 may predispose different neuron types to degeneration and then other genetic or external factors are required to produce the variable clinical phenotype. Taken together, our findings contribute to the current concept that familial FTD and ALS represent complex diseases, in which modifying genes and environmental agents can contribute to the risk of disease.