Cytoplasmic dynein plays critical roles within the developing and mature nervous systems, including effecting nuclear migration, and retrograde transport of various cargos. Unsurprisingly, mutations in dynein are causative of various developmental neuropathies and motor neuron diseases. These ‘dyneinopathies’ define a broad spectrum of diseases with no known correlation between mutation identity and disease state. To circumvent complications associated with dynein studies in human cells, we employed budding yeast as a screening platform to characterize the motility properties of seventeen disease-correlated dynein mutants. Using this system, we determined the molecular basis for several classes of etiologically related diseases. Moreover, by engineering compensatory mutations, we alleviated the mutant phenotypes in two of these cases, one of which we confirmed with recombinant human dynein. In addition to revealing molecular insight into dynein regulation, our data provide additional evidence that the type of disease may in fact be dictated by the degree of dynein dysfunction.

Cytoplasmic dynein plays critical roles within the developing and mature nervous systems, including effecting nuclear migration, and retrograde transport of various cargos. Unsurprisingly, mutations in dynein are causative of various developmental neuropathies and motor neuron diseases. These "dyneinopathies" define a broad spectrum of diseases with no known correlation between mutation identity and disease state. To overcome complications associated with studying dynein function in human cells, we employed budding yeast as a screening platform to characterize the motility properties of seventeen disease-correlated dynein mutants. Using this system, we have determined the molecular basis for several broad classes of etiologically related diseases. Moreover, by engineering compensatory mutations, we have alleviated the mutant phenotypes in two of these cases, one of which we confirmed with recombinant human dynein complexes. In addition to revealing molecular insight into dynein regulation, our data reveal an unexpected correlation between the degree of dynein dysfunction and disease type.3

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