• neuromuscular disease

This report describes neuromuscular disease, DCTN1-related. The human gene implicated in this disease is DCTN1, which encodes dynactin 1 (p150, Glued (Drosophila) homolog), the largest polypeptide of the dynactin complex. There is one high-scoring fly ortholog, DCTN1-p150, for which multiple genetic reagents, including RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles, have been generated. DCTN1 is also associated with the diseases Perry syndrome (MIM:168605, FBhh0000114) and distal hereditary motor neuronopathy, type VIIB (HMN7B; MIM:607641; FBhh0000147), and with an increased susceptibility to amyotrophic lateral sclerosis (MIM:105400, FBhh0000002). There is a second, moderate-scoring, ortholog in flies, Dred, for which which RNAi targeting constructs have been generated.

Multiple UAS constructs of the human Hsap\DCTN1 gene have been introduced into flies, including wild-type and constructs carrying a mutational lesion implicated in human disease. See the 'Disease-Implicated Variants' table below. Strong pan-neuronal overexpression of the wild-type human gene is toxic; low-level expression allows heterologous rescue (functional complementation) of the larval lethal phenotype of DCTN1-p150 amorphic mutations; however, the rescued adults are sterile.

Targeted RNAi knockdown of Dmel\DCTN1-p150 in either neurons or muscles results in climbing and flight defects in adult flies, while global knockdown results in significant reduction of larval mobility, neuromuscular junction defects, and death at pupal stages. Targeted RNAi knockdown of Dmel\Dred in muscles or motor neurons also results in motor impairments (FBrf0256871). These results support the hypothesis that loss-of-function variants of DCTN1 contribute to susceptibility to amyotrophic lateral sclerosis.

[updated Mar. 2024 by FlyBase; FBrf0222196]