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Objective  How hexanucleotide (GGGGCC) repeat expansions in  C9ORF72  cause amyotrophic lateral sclerosis (ALS) remains poorly understood. Both gain‐ and loss‐of‐function mechanisms have been proposed. Evidence supporting these mechanisms in vivo is, however, incomplete. Here we determined the effect of C9orf72 loss‐of‐function in mice.    Methods  We generated and analyzed a conditional  C9orf72  knockout mouse model.  C9orf72 fl/fl   mice were crossed with  Nestin‐Cre  mice to selectively remove C9orf72 from neurons and glial cells. Immunohistochemistry was performed to study motor neurons and neuromuscular integrity, as well as several pathological hallmarks of ALS, such as gliosis and TDP‐43 mislocalization. In addition, motor function and survival were assessed.    Results  Neural‐specific ablation of C9orf72 in conditional  C9orf72  knockout mice resulted in significantly reduced body weight but did not induce motor neuron degeneration, defects in motor function, or altered survival.    Interpretation  Our data suggest that  C9orf72  loss‐of‐function, by itself, is insufficient to cause motor neuron disease. These results may have important implications for the development of therapeutic strategies for C9orf72‐associated ALS. Ann Neurol 2015;78:426–438

C 9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits