A mutation in the gene DCTN1, which encodes the p150 subunit of dynactin, was identified in a family with an autosomal dominant lower motor neuron disease. The mutation, G59S, occurs in the CAP-Gly motif of the p150 subunit and is predicted to distort the folding of the microtubule-binding domain of dynactin. This mutation reduces the binding of dynactin to microtubules, leading to impaired axonal transport and potentially contributing to motor neuron disease. The study shows that dysfunction of dynactin-mediated transport can lead to human motor neuron disease. Motor neuron death occurs in various diseases affecting upper and lower motor neurons, with defects in axonal transport being implicated. Mutations in genes encoding kinesin motor proteins have been associated with motor neuron diseases. The G59S mutation in DCTN1 was found to be linked to a 4 Mb region on chromosome 2p13. The mutation was not found in unaffected family members or in 200 control individuals, suggesting it is pathogenic. The G59S mutation reduces the affinity of DCTN1 for microtubules, consistent with the late onset and mild progression of the disease. The dynactin complex is essential for retrograde transport of vesicles and organelles along microtubules. Overexpression of dynamitin, a subunit of dynactin, disrupts the complex and causes motor neuron disease in transgenic mice. Mutations in the Drosophila homolog of DCTN1 also produce severe phenotypes. The identification of the G59S mutation in DCTN1 demonstrates that dysfunction of a protein involved in retrograde transport can cause human motor neuron disease. Primary motor neurons may be particularly vulnerable to defects in axonal transport due to their size, metabolic activity, and dependence on trophic factors. Further studies may clarify whether the disease is caused by impaired transport of specific factors or by a more general effect. Other members of the dynactin-dynein complex may now be considered candidates for disruption in other hereditary and sporadic disorders with motor neuron degeneration.A mutation in the gene DCTN1, which encodes the p150 subunit of dynactin, was identified in a family with an autosomal dominant lower motor neuron disease. The mutation, G59S, occurs in the CAP-Gly motif of the p150 subunit and is predicted to distort the folding of the microtubule-binding domain of dynactin. This mutation reduces the binding of dynactin to microtubules, leading to impaired axonal transport and potentially contributing to motor neuron disease. The study shows that dysfunction of dynactin-mediated transport can lead to human motor neuron disease. Motor neuron death occurs in various diseases affecting upper and lower motor neurons, with defects in axonal transport being implicated. Mutations in genes encoding kinesin motor proteins have been associated with motor neuron diseases. The G59S mutation in DCTN1 was found to be linked to a 4 Mb region on chromosome 2p13. The mutation was not found in unaffected family members or in 200 control individuals, suggesting it is pathogenic. The G59S mutation reduces the affinity of DCTN1 for microtubules, consistent with the late onset and mild progression of the disease. The dynactin complex is essential for retrograde transport of vesicles and organelles along microtubules. Overexpression of dynamitin, a subunit of dynactin, disrupts the complex and causes motor neuron disease in transgenic mice. Mutations in the Drosophila homolog of DCTN1 also produce severe phenotypes. The identification of the G59S mutation in DCTN1 demonstrates that dysfunction of a protein involved in retrograde transport can cause human motor neuron disease. Primary motor neurons may be particularly vulnerable to defects in axonal transport due to their size, metabolic activity, and dependence on trophic factors. Further studies may clarify whether the disease is caused by impaired transport of specific factors or by a more general effect. Other members of the dynactin-dynein complex may now be considered candidates for disruption in other hereditary and sporadic disorders with motor neuron degeneration.