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J. Biol. Chem., Vol. 283, Issue 9, 5518-5524, February 29, 2008

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Mutations Causing DOK7 Congenital Myasthenia Ablate Functional Motifs in Dok-7^*

Johko Hamuro¹, Osamu Higuchi¹, Kumiko Okada, Makiko Ueno, Shun-ichiro Iemura, Tohru Natsume, Hayley Spearman^¶, David Beeson^¶, and Yuji Yamanashi²

From the Department of Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Yushima, Tokyo 113-8510, Japan, National Institute of Advanced Industrial Science and Technology, Biological Information Research Center, Kohtoh-ku, Aomi, Tokyo 135-0064, Japan, and ^¶Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom

Dok-7 is a cytoplasmic activator of muscle-specific receptor-tyrosine kinase (MuSK). Both Dok-7 and MuSK are required for neuromuscular synaptogenesis. Mutations in DOK7 underlie a congenital myasthenic syndrome (CMS) associated with small and simplified neuromuscular synapses likely due to impaired Dok-7/MuSK signaling. The overwhelming majority of patients with DOK7 CMS have at least one allele with a frameshift mutation that causes a truncation in the COOH-terminal region of Dok-7 and affects MuSK activation. Dok-7 has pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains in the NH₂-terminal moiety, both of which are indispensable for MuSK activation in myotubes, but little is known about additional functional elements. Here, we identify a chromosome region maintenance 1-dependent nuclear export signal (NES) in the COOH-terminal moiety and demonstrate that the NES-mediated cytoplasmic location of Dok-7 is essential for regulating the interaction with MuSK in myotubes. The NH₂-terminal PH domain is responsible for the nuclear import of Dok-7. We also show that the Src homology 2 target motifs in the COOH-terminal moiety of Dok-7 are active and crucial for MuSK activation in myotubes. In addition, CMS-associated missense mutations found in the PH or PTB domain inactivate Dok-7. Together, these findings demonstrate that, in addition to the NH₂-terminal PH and PTB domains, the COOH-terminal NES and Src homology 2 target motifs play key roles in Dok-7/MuSK signaling for neuromuscular synaptogenesis. Ablation or disruption of these functional elements in Dok-7 probably underlies the neuromuscular junction synaptopathy observed in DOK7 CMS.

Received for publication, October 17, 2007 , and in revised form, December 10, 2007.

^* This work was supported by grants-in-aid for Scientific research from the ministry of Education, Culture, Sports, Science, and Technology, Japan, grants from the Uehara Memorial, Mochida Memorial, and the Sumitomo foundations, and by the Medical Research Council and Muscular Dystrophy Campaign/Myasthenia Gravis Association of Great Britain. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Both authors equally contributed to this work.

² To whom correspondence should be addressed. Tel.: 81-3-5803-5814; Fax: 81-3-5803-0241; E-mail: yamanashi.creg{at}mri.tmd.ac.jp.

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