The long-term goals of this project are to understand the molecular basis for a group of closely related congenital myopathies and muscular dystrophies, and to use this information to develop therapies for patients with these debilitating conditions. X-linked myotubular myopathy (XLMTM) is caused by mutations of the MTM1 gene, which encodes myotubularin, an enzyme lipid phosphatase important for biogenesis and function of T tubules, which are the structures in skeletal muscles responsible for transmitting the signal to contract to the contractile apparatus. The centronuclear myopathies (CNMs), of which XLMTM is a subtype, also include forms caused by mutations in the RYR1, DNM2, and BIN1 genes, which are all known or thought to play a role in excitation contraction coupling (ECC) at the triads. Some families with CNM have mutations in genes that have yet to be identified.
The specific aims of this proposal are 1) to conduct studies designed to evaluate the potential for myostatin-inhibition therapy in a mouse model of XLMTM and 2) to complete the identification of the various genes that cause human CNMs and related myopathies. Each of the genes shown to cause a form of human CNM will then 3) be modeled in existing or new targeted zebrafish mutants, and 4) these lines will be characterized and developed for use in high throughput drug screens to identify lead compounds with therapeutic potential for these and related disorders of ECC in patients with primary myopathies and muscular dystrophies. The successful conclusion of these studies will result in development of accurate genetic tests to diagnose these conditions in affected children and family members, allowing for reliable family planning to avoid the birth of additional affected children. Furthermore, the identification of new drugs and small molecules that slow or prevent the development of weakness in the mouse and zebrafish models used in this study will set the stage for preclinical testing of new therapies that may one day be used to treat children with these devastating neuromuscular diseases.

Public Health Relevance

Neuromuscular diseases, such as the centronuclear myopathies that are the focus of this proposal, lead to severe skeletal muscle weakness, inability to walk, difficulty in conduct of daily activities, and premature death, often in infancyor early childhood. Genes and therapies for centronuclear myopathies is highly relevant to public health because it will result in identification of the remaining genes responsible for these conditions, allowing for accurate diagnosis, early detection of disease, and prenatal diagnosis to help families ensure the birth of healthy children. In addition, through the use of innovative mouse and zebrafish models, new drugs and therapies will be identified and tested, leading to development of future treatments for children and adults born with these crippling diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR044345-15A1
Application #
8438613
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Nuckolls, Glen H
Project Start
1996-12-15
Project End
2018-01-31
Budget Start
2013-02-08
Budget End
2014-01-31
Support Year
15
Fiscal Year
2013
Total Cost
$369,750
Indirect Cost
$157,250
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Childers, Martin K; Beggs, Alan H; Buj-Bello, Ana (2015) Gene replacement rescues severe muscle pathology and prolongs survival in myotubularin-deficient mice and dogs. Ann Transl Med 3:257
Goddard, Melissa A; Mack, David L; Czerniecki, Stefan M et al. (2015) Muscle pathology, limb strength, walking gait, respiratory function and neurological impairment establish disease progression in the p.N155K canine model of X-linked myotubular myopathy. Ann Transl Med 3:262
Sarwal, Aarti; Cartwright, Michael S; Walker, Francis O et al. (2014) Ultrasound assessment of the diaphragm: Preliminary study of a canine model of X-linked myotubular myopathy. Muscle Nerve 50:607-9

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