Mutations causing DOK7 congenital myasthenia ablate functional motifs in Dok-7.

Full Abstract

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.

Author information

Author/s: Hamuro, Johko (J); Higuchi, Osamu (O); Okada, Kumiko (K); Ueno, Makiko (M); Iemura, Shun-ichiro (S); Natsume, Tohru (T); Spearman, Hayley (H); Beeson, David (D); Yamanashi, Yuji (Y);

Affiliation: Department of Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Yushima, Tokyo 113-8510, Japan.

Grants: (Agency:Medical Research Council)

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: The Journal of biological chemistry (J Biol Chem), published in United States. (Language: eng)

Reference: 2008-Feb; vol 283 (issue 9) : pp 5518-24

Dates: Created 2008/02/25; Completed 2008/04/15; Revised 2008/11/21;

PMID: 18165682, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Alleles
Amino Acid Motifs - genetics
Animals
Cell Line
Enzyme Activation - genetics
Frameshift Mutation
Humans
Mice
Muscle Fibers, Skeletal - metabolism; pathology

Muscle Proteins - genetics; metabolism
Myasthenia Gravis - genetics; metabolism; pathology
Neuromuscular Junction - genetics; metabolism; pathology
Nuclear Localization Signals - genetics; metabolism
Protein Structure, Tertiary - genetics
Receptor Protein-Tyrosine Kinases - genetics; metabolism
Receptors, Cholinergic - genetics; metabolism
Signal Transduction - genetics
Syndrome

Associated Chemicals: DOK7 protein, human (0) ; Muscle Proteins (0) ; Nuclear Localization Signals (0) ; Receptors, Cholinergic (0) ; Receptor Protein-Tyrosine Kinases (EC 2.7.1.112) ; MUSK protein, human (EC 2.7.10.1) ; MuSK protein, mouse (EC 2.7.10.1)

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