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International Conference on Myasthenia Dok-7, MuSK, and the development of the neuromuscular junction Yuji Yamanashi Dept. Genetics Inst. Medical Science.

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Presentation on theme: "International Conference on Myasthenia Dok-7, MuSK, and the development of the neuromuscular junction Yuji Yamanashi Dept. Genetics Inst. Medical Science."— Presentation transcript:

1 International Conference on Myasthenia Dok-7, MuSK, and the development of the neuromuscular junction Yuji Yamanashi Dept. Genetics Inst. Medical Science University of Tokyo Paris, December 1-2, 2009

2 International Conference on Myasthenia Dok-7, MuSK, and the development of the neuromuscular junction Paris, December 1-2, The receptor protein-tyrosine kinase MuSK controls where the NMJ develops. 2.The cytoplasmic, adaptor-like protein Dok-7 is an essential activator of MuSK

3 The receptor protein-tyrosine kinase (PTK) MuSK PTK domain (catalytic domain) Frizzled-like cystein-rich domain ( Wnt response ? ) Ig-like domains (Agrin response) (Jennings et al., PNAS. 90: , 1993) 1.MuSK is essential for the development of NMJs 2.MuSK controls where NMJs form in myotubes (Kim et al., Nat. Neurosci. 11: 19-27, 2008) (DeChiara et al., Cell 85: , 1996) (Zhang et al., Develop. Cell. 16: , 1993)

4 ( E18.5 Diaphragm ) AChR cluster ( postsynaptic region ) MuSK is expressed in the central region of myotubes. Myotube AChR Nerve AChRs form postsynaptic clusters in the central region of the muscle Wild-type AChRs form postsynaptic clusters (red) in the central region of myotubes.

5 MuSK Tg (overexpression in the muscle) Uniformly overexpressed MuSK induces scattered AChR cluster formation; and NMJs are also scattered. AChR cluster ( postsynaptic region ) Myotube (Kim et al., Nat. Neurosci. 11: 19-27, 2008) AChR Nerve MuSK controls where the NMJs form Wild-type AChRs form postsynaptic clusters in the central region of myotubes. ( E18.5 Diaphragm )

6 AChR Nerve (Kim et al., Nat. Neurosci. 11: 19-27, 2008) MuSK KO MuSK-KO mice form no AChR cluster ( Diaphragm ) (Lin et al., Nature 410: , 2001) MuSK controls where the NMJs form AChR cluster ( postsynaptic region ) Myotube MuSK Tg (overexpression in the muscle) Uniformly overexpressed MuSK induces scattered AChR cluster formation; and NMJs are also scattered. Wild-type AChRs form postsynaptic clusters (red) in the central region of myotubes.

7 AChR MuSK AChR cluster Myotube Rapsyn motor nerve Agrin Motor nerve terminal motor nerve terminal Agrin LRP4LRP4 LRP4LRP4 LRP4LRP4 LRP4LRP4 Neural Agrin activates MuSK via LRP4 coreceptor. (Kim et al., Cell 135: , 2008) (Zhang et al., Neuron 60: , 2008)

8 AChR MuSK AChR cluster Myotube Rapsyn motor nerve Agrin Motor nerve terminal motor nerve terminal Agrin LRP4LRP4 LRP4LRP4 LRP4LRP4 LRP4LRP4 AChR Nerve HB9 KO WT MuSK KO Agrin KO AChR Nerve Nerve/Agrin-independent but MuSK-dependent AChR clustering ( Lin et al, Nature 410: , 2001) (E14.5 Diaphragm)

9 AChR MuSK AChR cluster Myotube Rapsyn motor nerve Agrin LRP4LRP4 LRP4LRP4 LRP4LRP4 LRP4LRP4 AChR Nerve HB9 KO WT MuSK KO Agrin KO AChR Nerve Nerve/Agrin-independent but MuSK-dependent AChR clustering ( Lin et al, Nature 410: , 2001) (E14.5 Diaphragm) ( ) Nerve/Agrin-independent, probably muscle-intrinsic element(s) may exist to activate MuSK ?

10 AChR MuSK AChR cluster Myotube Rapsyn motor nerve Agrin LRP4LRP4 LRP4LRP4 LRP4LRP4 LRP4LRP4 AChR Nerve HB9 KO WT MuSK KO Agrin KO AChR Nerve Nerve/Agrin-independent but MuSK-dependent AChR clustering ( Lin et al, Nature 410: , 2001) (E14.5 Diaphragm) Dok-7 Nerve/Agrin-independent, probably muscle-intrinsic element(s) may activate MuSK

11 High expression in hematopoietic cells High expression in non-hematopoietic cells Dok-family High expression in muscles Y: SH2 binding/target motif PHPTB YYYY PHPTB YYY PHPTB YYYYY PHPTB PHPTB PHPTB YYYY YYYYYY YYYY YYYYYY ( 35%) ( - - -) ( 35%) ( - - -) ( 30%) ( - - -) ( 40%) ( 50%) ( 40%) (100%) Dok-1 (62kD) Dok-2 (56kD) Dok-3 (58kD) Dok-4 (41kD) Dok-5 (36kD) Dok-6 (36kD) PHPTB YY ( 20%)( - - -) Dok-7 (55kD)

12 Dok-1/2 Ras- Erk (Proliferation & Cytokine Production) Yamanashi & Baltimore, Cell, 1997 Yamanashi et al., Genes Dev., 2000 Yasuda et al., J. Exp. Med., 2004, Shinohara et al., J. Exp. Med., 2005 GM-CSFR IL-3R TLR4 BCR SCFR M-CSFR Non-Receptor PTKs Receptor PTKs Dok-1/2

13 High expression in hematopoietic cells High expression in non-hematopoietic cells Dok-family proteins High expression in muscles Y: SH2 binding/target motif PHPTB YYYY PHPTB YYY PHPTB YYYYY PHPTB PHPTB PHPTB YYYY YYYYYY YYYY YYYYYY ( 35%) ( - - -) ( 35%) ( - - -) ( 30%) ( - - -) ( 40%) ( 50%) ( 40%) (100%) Dok-1 (62kD) Dok-2 (56kD) Dok-3 (58kD) Dok-4 (41kD) Dok-5 (36kD) Dok-6 (36kD) ( Okada et al., Science, 2006 ) PHPTB YY ( 20%)( - - -) Dok-7 (55kD)

14 Postsynaptic localization of Dok-7 at Neuromuscular Junction (NMJ) NMJ (Neuromuscular Junction) gastrocnemius myotube AChR (ACh receptor) cluster Presynaptic vesicle (+ACh: acetylcholine) Merge AChRDok-7 (  -Dok-7 Ab) (bungarotoxin) (Apel et al., Neuron, 1997) AChRMuSK NMJ myotube motor nerve

15 AChR MuSK AChR cluster Myotube Rapsyn motor nerve Agrin Motor nerve terminal motor nerve terminal Agrin LRP4LRP4 LRP4LRP4 LRP4LRP4 LRP4LRP4 ? ? Dok-7 PH PTB Y Y Y Y PH PTB Postsynaptic localization of Dok-7 at Neuromuscular Junction (NMJ) NMJ (Neuromuscular Junction) gastrocnemius myotube AChR (ACh receptor) cluster Presynaptic vesicle (+ACh: acetylcholine) Merge AChR (bungarotoxin) Dok-7 (  -Dok-7 Ab) Agrin-MuSK -Dok-7 signaling ?

16 Dok-7 induces MuSK activation and AChR clustering in myotubes Dok-7 ( ) AChR myotubes ( C2C12 ) ( AChR : ACh Receptor )  pY / Dok-7  MuSK  pY  P   MuSK AChR-PD WCL   pY-AChR  1  Dok-7  Tubulin IP : Immunoprecipitation IB : Immunoblotting PD : Pull-down WCL : Whole cell lysates  pY : anti-phosphotyrosine myotubes

17 AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Agrin Dok-7 can activate MuSK independently of Agrin Dok-7 induces MuSK activation and AChR clustering in myotubes Dok-7 ( ) AChR myotubes ( C2C12 )  pY / Dok-7  MuSK  pY  P   MuSK AChR-PD WCL   pY-AChR  1  Dok-7  Tubulin Dok-7 PH Y Y PTB Y Y PH PTB

18 AChR MuSK AChR cluster Myotube Rapsyn motor nerve Agrin LRP4LRP4 LRP4LRP4 LRP4LRP4 LRP4LRP4 AChR Nerve HB9 KO WT MuSK KO Agrin KO AChR Nerve Nerve/Agrin-independent but MuSK-dependent AChR clustering ( Lin et al, Nature 410: , 2001) (E14.5 Diaphragm) Dok-7 Nerve/Agrin-independent, probably muscle-intrinsic element(s) may activate MuSK

19 AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Is Dok-7 a muscle-intrinsic activator of MuSK in vivo ? Dok-7 PH Y Y PTB Y Y PH PTB Agrin Dok-7 can activate MuSK independently of Agrin

20 (E18.5 diaphragm) WT Merge AChR Dok-7 KO AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB motor nerve Agrin LRP4LRP4 LRP4LRP4 Dok-7 is essential for AChR clustering and NMJ formation in vivo Nerve (E14.5 diaphragm) WT Merge AChR Dok-7 KO Nerve E14.5

21 AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB motor nerve Agrin LRP4LRP4 LRP4LRP4 Overexpression of Dok-7 in vivo WT Tg IP: Dok-7 IB: Dok-7 E Dok-7- EGFP Dok-7

22 ( Inoue et al. Science Signaling, 2009 ) AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB motor nerve Agrin LRP4LRP4 LRP4LRP4 Overexpression of Dok-7 in vivo facilitates AChR cluster formation E18.5 Diaphragm Dok-7 Tg AChR WT Merge WT Tg IP: Dok-7 IB: Dok-7 E Dok-7- EGFP Dok-7 Nerve

23 AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB motor nerve Agrin LRP4LRP4 LRP4LRP4 Overexpression of Dok-7 in vivo facilitates AChR cluster formation Myofibers (%) AChR clusters per myofiber WT Dok-7 Tg 789 ( Inoue et al. Science Signaling, 2009 ) E18.5 Diaphragm Dok-7 Tg AChR WT Merge Nerve

24 AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB motor nerve Agrin LRP4LRP4 LRP4LRP4 Overexpression of Dok-7 in vivo facilitates AChR cluster formation ( Inoue et al. Science Signaling, 2009 ) E18.5 Diaphragm Dok-7 Tg AChR WT Merge Nerve Dok-7 Tg WT AChR cluster(s) on a myotube

25 AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB motor nerve Agrin LRP4LRP4 LRP4LRP4 Dok-7 induces NMJ formation in vivo Overexpression of Dok-7 in vivo facilitates NMJ formation Number of NMJs (% of WT ) Dok-7 TgWT E18.5 ** P < ** ( Inoue et al. Science Signaling, 2009 ) Dok-7 Tg WT AChR cluster(s) on a myotube

26 AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB motor nerve Agrin LRP4LRP4 LRP4LRP4 Dok-7 is an essential activator of MuSK Dok-7 activates MuSK in vivo IB: PY IB: MuSK IP: MuSK WT Tg pY-MuSK MuSK 100 IB: PY IB: AChR (  Tg Dok-7 +/+ -/- -/- +/+ pY-AChR AChR AChR-PD (Btx) 50 pY-MuSK *P < 0.05 Dok-7 TgWT * Relative intensity **P < pY-AChR Dok-7 TgWT ** Relative intensity ( Inoue et al. Science Signaling, 2009 )

27 AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB LRP4LRP4 LRP4LRP4 Dok-7 is an essential activator of MuSK Agrin motor nerve (E14.5 diaphragm) AChR HB9 KO WT MuSK KO Agrin KO ( Lin et al, Nature 410: , 2001) Nerve

28 AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB motor nerve Agrin LRP4LRP4 LRP4LRP4 Why Agrin cannot induce AChR clustering in Dok-7 KO mice? (E18.5 diaphragm) WT Merge AChR Dok-7 KO Nerve (E14.5 diaphragm) WT Merge AChR Dok-7 KO Nerve E14.5

29 AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB motor nerve Agrin LRP4LRP4 LRP4LRP4 Dok-7 may be required for Agrin-mediated MuSK activation (E18.5 diaphragm) WT Merge AChR Dok-7 KO Nerve (E14.5 diaphragm) WT Merge AChR Dok-7 KO Nerve E14.5

30 AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB Agrin LRP4LRP4 LRP4LRP4 Dok-7 is required for Agrin-mediated MuSK activation ( myotube ) WTDok-7 -/- IP: MuSK IB: pY IB: MuSK Agrin (min)

31 AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB Agrin LRP4LRP4 LRP4LRP4 Dok-7 is required for Agrin-mediated MuSK activation ( Inoue et al. Science Signaling, 2009 ) WT Dok-7 -/- Dok-7 -/- + Dok-7 AChR Agrin (-)Agrin (+) ( myotube ) WTDok-7 -/- IP: MuSK IB: pY IB: MuSK Agrin (min)

32 AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB WT MuSK KO Agrin KO ( Lin et al, Nature 410: , 2001) (E18.5 diaphragm) Dok-7 KO motor nerve Dok-7 is a key muscle-intrinsic activator of MuSK AChR Nerve Merge AChR Nerve Agrin LRP4LRP4 LRP4LRP4

33 AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB LRP4LRP4 LRP4LRP motor nerve How does Dok-7 activate MuSK from the cytoplasmic compartment ? Dok-7 is a key muscle-intrinsic activator of MuSK

34 AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB LRP4LRP4 LRP4LRP motor nerve How does Dok-7 activate MuSK from the cytoplasmic compartment ? Dok-7 is a key muscle-intrinsic activator of MuSK ?

35 The ectodmain of MuSK is dispensble for Dok-7-mediated activation Dok-7 Y Y PH PTB MuSK-  Ig Dok-7 may target the cytoplasmic portion of MuSK Dok-7 MuSK + IB:  pY + WT  Ig (293T cells) IB:  Dok-7 IB:  myc (MuSK) ( Inoue et al. Science Signaling, 2009 ) pY-MuSK pY-MuSK-  Ig WT MuSK-  Ig DOK-7

36 IB:  pY pY-MuSK pY-MuSK-  Ig pY-MuSK-Cyt + Dok-7 Y Y PH PTB MuSK-Cyt (293T cells) IB:  Dok-7 IB:  myc (MuSK) WT MuSK-  Ig MuSK-Cyt DOK-7 Dok-7 Y Y PH PTB MuSK-  Ig Cyt ( Inoue et al. Science Signaling, 2009 ) The ectodmain and transmembrane region of MuSK are dispensble for Dok-7-mediated activation Dok-7 MuSK + + WT  Ig

37 Dok-7 targets the cytoplasmic portion of MuSK Dok-7 Y Y PH PTB MuSK-Cyt AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB LRP4LRP4 LRP4LRP4 The ectodmain and transmembrane region of MuSK are dispensble for Dok-7-mediated activation IB:  pY pY-MuSK pY-MuSK-  Ig pY-MuSK-Cyt + Cyt Dok-7 MuSK + + WT  Ext

38 Dok-7 targets the cytoplasmic portion of MuSK AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB LRP4LRP4 LRP4LRP4 Does Dok-7 directly activate the cytoplasmic portion of MuSK?

39 Dok-7 targets the cytoplasmic portion of MuSK AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB LRP4LRP4 LRP4LRP4 (kDa) MuSK-cyt Dok-7 (CBB) Dok-7 Y Y PH PTB MuSK- Cyt

40 AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB LRP4LRP4 LRP4LRP4 Dok-7 directly activates the cytoplasmic portion of MuSK Dok-7 Y Y PH PTB MuSK- Cyt ( Inoue et al. Science Signaling, 2009 ) MuSK-cyt pY-Dok-7-His pY-MuSK-cyt IB: pY IB: pY (min) MuSK-cyt + Dok-7 pY: phosphotyrosine

41 AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB LRP4LRP4 LRP4LRP4 Dok-7 directly activates the cytoplasmic portion of MuSK MuSK-cyt + Dok-7  N pY-MuSK-cyt IB: pY (min) Dok-7 Y Y PH PTB MuSK- Cyt ( Inoue et al. Science Signaling, 2009 ) MuSK-cyt pY-Dok-7-His pY-MuSK-cyt IB: pY IB: pY (min) MuSK-cyt + Dok-7 pY: phosphotyrosine

42 ( Inoue et al. Science Signaling, 2009 ) E18.5 Diaphragm Dok-7 Tg WT Merge AChR Dok-7 Tg WT Overexpression of Dok7 * Myotube AChR cluster ( postsynaptic region ) AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB motor nerve Agrin LRP4LRP4 LRP4LRP4 Why uniform overexpression of Dok-7 facilitates centrally formation of the NMJ ? Nerve

43 ( Inoue et al. Science Signaling, 2009 ) E18.5 Diaphragm Dok-7 Tg WT Merge AChR Nerve Dok-7 Tg WT Overexpression of Dok7 * Myotube AChR cluster ( postsynaptic region ) Is MuSK expressed in the central region of Dok-7 Tg muscle?

44 (Diaphragm) in situ hybrid. MuSK is expressed in the central region of Dok-7 Tg muscle, and Dok-7 is required for the centrally restricted expression of MuSK and AChR MuSK E14.5 E18.5 Dok-7 -/- WTDok-7Tg AChR  Dok-7 -/- WTDok-7Tg E14.5 E18.5 Dok-7 is essential for mid-muscle expression of MuSK and AChR

45 (Diaphragm) in situ hybrid. MuSK E14.5 E18.5 Dok-7 -/- WTDok-7Tg AChR  Dok-7 -/- WTDok-7Tg E14.5 E18.5 Dok-7 is essential for mid-muscle expression of MuSK and AChR scale bar: 100  m (Diaphragm) Immunostaining

46 AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB LRP4LRP4 LRP4LRP4 Dok-7 regulates the mid-muscle NMJ formation by controlling MuSK activity, expression pattern, and responsiveness to Agrin. (Diaphragm) in situ hybrid. MuSK E14.5 E18.5 Dok-7 -/- WTDok-7Tg AChR  Dok-7 -/- WTDok-7Tg E14.5 E18.5 Dok-7 is essential for mid-muscle expression of MuSK and AChR

47 A simplified model of Dok-7-MuSK-Agrin signaling in the NMJ formation MuSK Dok-7 MuSK Agrin AChR MuSK Dok-7 MuSK Motor nerve Dok-7 is expressed in the central region of skeletal muscle, where it activates MuSK and induces MuSK’s mid-muscle pattern formation. Activated MuSK induces postsynaptic specialization in the central region of muscle independently of nerve and Agrin. ACh disperses non-innervated AChR clusters but the local mediator Agrin fully activates Dok-7-primed/activated MuSK and counteracts ACh. Dok-7-MuSK-Agrin triad signaling promotes and reinforces NMJ formation. Rapsyn LRP4 Agrin Motor nerve Ⅰ Ⅱ Ⅲ Ⅳ ACh (myotube) ACh

48

49 Dok-7 Tg WT ( Inoue et al. Science Signaling, 2009 ) AChR MuSK AChR cluster Myotube Rapsyn LRP4LRP4 LRP4LRP4 Dok-7 PH PTB Y Y Dok-7 PH Y Y PTB Y Y PH PTB motor nerve Agrin LRP4LRP4 LRP4LRP4 Dok-7 Tg rescues NMJs in Dok KO mice AChR NerveMerge Dok-7 -/- WT Dok-7 -/- + Dok-7 Tg E14.5 Diaphragm (unpublished) AChR NerveMerge

50 International Conference on Myasthenia Dok-7, MuSK, and the development of the neuromuscular junction Paris, December 1-2, Dok-7 is an essential, muscle-intrinsic activator of MuSK, in NMJ development 2.Enhanced Dok-7 signaling may ameliorate DOK7 and MuSK-related myasthenia

51 Masakatsu Motomura Irokazu Shiraishi Katsumi Eguchi (Nagasaki Univ.) Takashi Okada Shin’ichi Takeda (Natl. Inst. Neurosci.) Shigeru Kakuta Sachiko Kubo Yoichiro Iwakura Takafumi Jigami Tetsu Akiyama (Univ. Tokyo) ・ Osamu Higuchi ・ Akane Inoue Kiyoko Setoguchi ・ Johko Hamuro ・ Kumiko Okada Collaborators David Beeson Jackie Palace Angela Vincent (Oxford Univ.) Peter Fawcett Clarke Slater (Univ. Newcastle) Juliane S. Muller Hanns Lochmuller (Ludwig-Maxim. Univ.) Frederic Chevessier Veit Witzemann (Max-Planck Inst. Med.) Daniel Hantai (Inserm, Inst. Myologie)


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