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J. Biol. Chem., Vol. 278, Issue 28, 26159-26165, July 11, 2003

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Truncation by Glu¹⁸⁰ Nonsense Mutation Results in Complete Loss of Slow Skeletal Muscle Troponin T in a Lethal Nemaline Myopathy^*

Jian-Ping Jin  , Marco A. Brotto , M. Moazzem Hossain , Qi-Quan Huang , Leticia S. Brotto , Thomas M. Nosek , D. Holmes Morton ¶ and Thomas O. Crawford ||

From the Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, the ^¶Clinic for Special Children, Strasburg, Pennsylvania 17579, and the ^||Departments of Neurology and Pediatrics, Johns Hopkins University, Baltimore, Maryland 21287

A lethal form of nemaline myopathy, named "Amish Nemaline Myopathy" (ANM), is linked to a nonsense mutation at codon Glu¹⁸⁰ in the slow skeletal muscle troponin T (TnT) gene. We found that neither the intact nor the truncated slow TnT protein was present in the muscle of patients with ANM. The complete loss of slow TnT is consistent with the observed recessive pattern of inheritance of the disease and indicates a critical role of the COOH-terminal T2 domain in the integration of TnT into myofibrils. Expression of slow and fast isoforms of TnT is fiber-type specific. The lack of slow TnT results in selective atrophy of type 1 fibers. Slow TnT confers a higher Ca²⁺ sensitivity than does fast TnT in single fiber contractility assays. Despite the lack of slow TnT, individuals with ANM have normal muscle power at birth. The postnatal onset and infantile progression of ANM correspond to a down-regulation of cardiac and embryonic splice variants of fast TnT in normal developing human skeletal muscle, suggesting that the fetal TnT isoforms complement slow TnT. These results lay the foundation for understanding the molecular pathophysiology and the potential targeted therapy of ANM.

Received for publication, April 3, 2003 , and in revised form, April 29, 2003.

^* This study was supported in part by NIAMS, National Institutes of Health Grant AR 048816 (to J.-P.J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 216-368-5525; Fax: 216-368-3952; E-mail: jxj12{at}po.cwru.edu.

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