Modeling the human MTM1 p.R69C mutation in murine Mtm1 results in exon 4 skipping and a less severe myotubular myopathy phenotype. Hum Mol Genet 2012 Feb 15;21(4):811-25
Date
11/10/2011Pubmed ID
22068590Pubmed Central ID
PMC3263994DOI
10.1093/hmg/ddr512Scopus ID
2-s2.0-84856350401 (requires institutional sign-in at Scopus site) 54 CitationsAbstract
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.
Author List
Pierson CR, Dulin-Smith AN, Durban AN, Marshall ML, Marshall JT, Snyder AD, Naiyer N, Gladman JT, Chandler DS, Lawlor MW, Buj-Bello A, Dowling JJ, Beggs AHAuthor
Michael W. Lawlor PhD, MD Adjunct Professor in the Pathology and Laboratory Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCalcium
Disease Models, Animal
Exons
Female
Genetic Association Studies
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle, Skeletal
Mutation, Missense
Myopathies, Structural, Congenital
Phenotype
Phosphatidylinositol Phosphates
Point Mutation
Protein Tyrosine Phosphatases, Non-Receptor
