X-linked myotubular myopathy (MTM) is a severe neuromuscular disease of infancy 
caused by mutations of MTM1, which encodes the phosphoinositide lipid 
phosphatase, myotubularin. The Mtm1 knockout (KO) mouse has a severe phenotype 
and its short lifespan (8 weeks) makes it a challenge to use as a model in the 
testing of certain preclinical therapeutics. Many MTM patients succumb early in 
life, but some have a more favorable prognosis. We used human genotype-phenotype 
correlation data to develop a myotubularin-deficient mouse model with a less 
severe phenotype than is seen in Mtm1 KO mice. We modeled the human c.205C>T 
point mutation in Mtm1 exon 4, which is predicted to introduce the p.R69C 
missense change in myotubularin. Hemizygous male Mtm1 p.R69C mice develop early 
muscle atrophy prior to the onset of weakness at 2 months. The median survival 
period is 66 weeks. Histopathology shows small myofibers with centrally placed 
nuclei. Myotubularin protein is undetectably low because the introduced c.205C>T 
base change induced exon 4 skipping in most mRNAs, leading to premature 
termination of myotubularin translation. Some full-length Mtm1 mRNA bearing the 
mutation is present, which provides enough myotubularin activity to account for 
the relatively mild phenotype, as Mtm1 KO and Mtm1 p.R69C mice have similar 
muscle phosphatidylinositol 3-phosphate levels. These data explain the basis for 
phenotypic variability among human patients with MTM1 p.R69C mutations and 
establish the Mtm1 p.R69C mouse as a valuable model for the disease, as its less 
severe phenotype will expand the scope of testable preclinical therapies.