A pathogenic peripherin gene mutation in a patient with amyotrophic lateral sclerosis.

Peripherin is a neuronal intermediate filament protein that is expressed chiefly in motor neurons and other nerve cells that project into the peripheral nervous system. Transgenic mice that over-express peripherin develop motor neuron degeneration, suggesting that mutations in peripherin could contribute to the development of motor neuron disease. In this paper, we report the identification of a homozygous mutation in the peripherin gene (PRPH) in a patient with amyotrophic lateral sclerosis (ALS). The mutation resulted in a substitution of aspartate with tyrosine at amino acid position 141, which is located within the first linker region of the rod domain. Immunocytochemical analysis of the spinal cord of the patient upon autopsy revealed distinctive large aggregates within the cell bodies of residual spinal motor neurons that contained peripherin and was also immunoreactive with antibodies to the neurofilament proteins. In order to study the effect of the mutation on peripherin assembly, we performed transient transfections. Unlike wild-type peripherin, which self-assembles to form a filamentous network, the mutant peripherin was prone to form aggregates in transfected cells, indicating that the mutation adversely affects peripherin assembly. Moreover, the neurofilament light (NF-L) protein was not able to rescue the mutant protein from forming aggregates. These data imply that mutation of PRPH is a contributing factor for ALS.