ライフサイエンスコーパス: dysferlin

1 ations in the DYSF gene encoding the protein dysferlin.

2 reases the levels of R555W mis-sense mutated dysferlin.

3 , mutations that lead to clinical disease in dysferlin.

4 to repair membrane damage in the absence of dysferlin.

5 defective membrane repair in the absence of dysferlin.

6 ssociation with the membrane repair protein, dysferlin.

7 sgene expression is specific to mice lacking dysferlin.

8 e induced by OSI and suppressed by exogenous dysferlin.

9 Mutations in the protein dysferlin, a member of the ferlin family, lead to limb g

10 LGMD 2B is caused by loss of dysferlin, a membrane repair protein, and LGMD 2C is cau

11 Dysferlin, a type-II transmembrane phospholipid-binding

12 onstituted lipid mixing assays indicate that dysferlin accelerates syntaxin 4/SNAP-23 heterodimer for

13 g sarcolemma, leading to formation of stable dysferlin accumulations surrounding lesions, endocytosis

14 Dysferlin and calpain are important mediators of the eme

15 Here we show that MG53 interacts with dysferlin and Cav3 to regulate membrane repair in skelet

16 Both lines of mice lacked dysferlin and developed a progressive muscular dystrophy

17 tal muscle after sarcolemmal damage involves dysferlin and dysferlin-interacting proteins such as ann

18 Myoferlin is highly homologous to dysferlin and like dysferlin is a plasma membrane protei

19 these findings demonstrate the importance of dysferlin and myoferlin for transverse tubule function a

20 een the C2A domain of otoferlin and those of dysferlin and myoferlin, and truncation studies suggest

21 We found that C2A, the first C2 domain of dysferlin and myoferlin, bound 50% phosphatidylserine an

22 ily, Fer1L5, because of its high homology to dysferlin and myoferlin.

23 vide insight into the structural topology of dysferlin and show how a single missense mutation within

24 gations that point to an interaction between dysferlin and the Ca2+ and lipid-binding proteins, annex

25 Dye influx into muscle fibers lacking both dysferlin and the related protein myoferlin was substant

26 we demonstrate a direct interaction between dysferlin and the SNARE proteins syntaxin 4 and SNAP-23.

27 etal muscle development and repair (MYOF and dysferlin), and presynaptic transmission in the auditory

28 eal that a molecular complex formed by MG53, dysferlin, and Cav3 is essential for repair of muscle me

29 ulations surrounding lesions, endocytosis of dysferlin, and formation of large cytoplasmic vesicles f

30 ective interplay between activated calpains, dysferlin, and L-type channels explains how muscle cells

31 s of binding of the C2 domains of otoferlin, dysferlin, and myoferlin on the structure of lipid bilay

32 hat multi-C2 domain constructs of myoferlin, dysferlin, and otoferlin change the lipid packing of bot

33 Although mutations in caveolin-3 (Cav3) and dysferlin are linked to muscular dystrophy in human pati

34 Mutations in dysferlin are linked to two clinically distinct muscle d

35 Myoferlin and dysferlin are members of the ferlin family of membrane p

36 embrane repair process and that mutations in dysferlin are responsible for limb girdle muscular dystr

37 These results support a function for dysferlin as a calcium-sensing SNARE effector for membra

38 Our discovery of dysferlin as a t-tubule protein that stabilizes stress-i

39 membrane repair cascade that elicits cleaved dysferlin as an effector.

40 inding properties of all seven C2 domains of dysferlin as well as a multi-C2 domain construct.

41 e phenotypic overlap of ANO5 myopathies with dysferlin-associated muscular dystrophies has inspired t

42 ture oocytes of the sea star, and identified dysferlin by mass spectrometry analysis.

43 rimetry measurements indicate that all seven dysferlin C2 domains interact with Ca(2+) with a wide ra

44 We demonstrate that the dysferlin C2B, C2C, C2D, and C2E domains are dispensable

45 normal muscle, membrane patches enriched in dysferlin can be detected in response to sarcolemma inju

46 d show how a single missense mutation within dysferlin can exert local changes in tertiary conformati

47 In the absence of dysferlin, cardiomyocyte membrane damage occurs and is l

48 primary pathogenesis and pathophysiology of dysferlin cardiomyopathy, we studied cardiac phenotypes

49 ion indicate a novel pathogenic mechanism of dysferlin cardiomyopathy.

50 Loss-of-function mutations in dysferlin cause muscular dystrophy, and dysferlin has be

51 Mutations in dysferlin cause the progressive muscular dystrophies Miy

52 Loss of dysferlin causes death of cardiomyocytes, notably in age

53 is a component of that system and absence of dysferlin causes muscular dystrophy (dysferlinopathy) ch

54 Regional expression of Venus-dysferlin chimeras in A/J fibres restored the full ampli

55 am65b is an essential component of the HDAC6-dysferlin complex.

56 ABSTRACT: Dysferlin concentrates in the transverse tubules of skel

57 ene transfer, we tested internally truncated dysferlin constructs, each lacking one of the seven C2 d

58 lemma to facilitate membrane repair, but the dysferlin-containing compartments involved in membrane r

59 recruitment of approximately 30 mum of local dysferlin-containing sarcolemma, leading to formation of

60 mine the role of microtubules and kinesin in dysferlin-containing vesicle behavior following wounding

61 d the role of the cytoskeleton in regulating dysferlin-containing vesicle biology is unclear.

62 resealing, and highlight a critical role for dysferlin-containing vesicle-vesicle and vesicle-organel

63 Membrane wounding induces dysferlin-containing vesicle-vesicle fusion and the form

64 mbrane resealing, and our data indicate that dysferlin-containing vesicles are capable of fusing with

65 live-cell imaging to examine the behavior of dysferlin-containing vesicles following cellular woundin

66 evidence that microtubule-based transport of dysferlin-containing vesicles may be critical for reseal

67 Our data indicate that dysferlin-containing vesicles move along microtubules vi

68 However, the contribution of dysferlin-containing vesicles to resealing in muscle and

69 d suggest multiple pathways by which loss of dysferlin contributes to muscle disease.

70 the degradation pathway of mis-sense mutated dysferlin could be used as a therapeutic strategy for pa

71 sm whereby recruitment of sarcolemma-derived dysferlin creates an active zone of high lipid-binding a

72 tution strains, should take into account the dysferlin defect in these strains.

73 in wild-type fibers, similar to findings in dysferlin deficiency (a 2-fold increase in FM1-43 uptake

74 Recent evidence suggests that dysferlin deficiency affects cardiac muscle, leading to

75 Dysferlin deficiency causes limb-girdle muscular dystrop

76 As dysferlin deficiency has been shown to enhance phagocyto

77 Though much is known about the effects of dysferlin deficiency in skeletal muscle, little is known

78 Dysferlin deficiency in the C57BL/6J background was asso

79 ed in cardiomyocyte membrane repair and that dysferlin deficiency leads to cardiomyopathy.

80 We have previously shown that dysferlin deficiency leads to defective membrane reseali

81 Dysferlin deficiency led to increased expression of comp

82 Muscle inflammation is often present in dysferlin deficiency, and patients are frequently misdia

83 Dysferlin deficiency-related persistence of mechanically

84 dystrophies caused by genetically determined dysferlin deficiency.

85 Mutations in the dysferlin gene resulting in dysferlin-deficiency lead to limb-girdle muscular dystro

86 Further, deletion of AnxA2 in dysferlin deficient mice reduced muscle inflammation, ad

87 effect of blocking the myostatin pathway in dysferlin-deficient (Dysf(-/-)) mice, in which membrane

88 The dysferlin-deficient A/J mouse develops a mild myopathy a

89 ough macrophage infiltration is prominent in dysferlin-deficient A/J muscle after LSI, it is the cons

90 s within the psoas and quadriceps muscles of dysferlin-deficient A/J(dys-/-) mice aged 8 and 12 month

91 By subjecting dysferlin-deficient B6.A/J-Dysf(prmd) mice to long-term

92 Similar results were seen for dysferlin-deficient BLAJ mice.

93 e specifically up-regulated and activated in dysferlin-deficient but not in dystrophin-deficient and

94 mice and increases Evans blue dye uptake in dysferlin-deficient cardiomyocytes.

95 Dysferlin-deficient cells show abnormalities in vesicula

96 udied the inflammasome molecular platform in dysferlin-deficient human and mouse muscle.

97 We used a dysferlin-deficient human myoblast culture harboring the

98 repair laser-induced plasmalemmal wounds in dysferlin-deficient human myoblasts.

99 ane damage and disturbed cardiac function in dysferlin-deficient mice (see the related article beginn

100 ement system ameliorated muscle pathology in dysferlin-deficient mice but had no significant benefici

101 contrast to the latter group of animals, the dysferlin-deficient mice have an intact dystrophin glyco

102 Here, we report two novel lines of dysferlin-deficient mice obtained by (a) gene targeting

103 These new dysferlin-deficient mice should be useful for elucidatin

104 Cardiomyocytes isolated from dysferlin-deficient mice showed normal shortening and re

105 , we demonstrate that diltiazem treatment of dysferlin-deficient mice significantly reduces eccentric

106 ral history and disease progression in these dysferlin-deficient mice up to 18 months of age and were

107 generating and also needle wounded muscle in dysferlin-deficient mice.

108 Dysferlin-deficient monocytes showed increased phagocyti

109 c pressure and stroke volume were blunted in dysferlin-deficient mouse hearts compared with that in w

110 Young dysferlin-deficient mouse hearts expressed normal isofor

111 onocytes from LGMD2B patients and in the SJL dysferlin-deficient mouse model.

112 for AAV-mediated gene therapy experiments in dysferlin-deficient mouse models.

113 ses RhoA, Rac1, and Cdc 42 were increased in dysferlin-deficient murine immune cells compared with co

114 membrane repair machinery is responsible for dysferlin-deficient muscle degeneration, and highlight t

115 owing experimental membrane stress in vitro, dysferlin-deficient muscle fibers undergo extensive func

116 Interestingly, dysferlin-deficient muscle fibres are defective in Ca2+-

117 we hypothesize that mild myofiber damage in dysferlin-deficient muscle stimulates an inflammatory ca

118 To identify molecular networks specific to dysferlin-deficient muscle that might explain disease pa

119 wound-healing are significantly disrupted in dysferlin-deficient muscle.

120 pid and progressive adipocyte replacement in dysferlin-deficient muscles present a new focus for inve

121 induction of lipogenesis/adipogenesis within dysferlin-deficient muscles.

122 air may contribute to disease progression in dysferlin-deficient muscular dystrophy.

123 ized that monocyte/macrophage dysfunction in dysferlin-deficient patients might contribute to disease

124 In addition, we show that dysferlin-deficient primary muscle cells express toll-li

125 This suggests that dysferlin deregulation in monocytes might contribute to

126 ellular patterning is evident as annexin A1, dysferlin, diacylglycerol, active Rho, and active Cdc42

127 However, overexpression of dysferlin did not improve dystrophic symptoms or membran

128 d deletion mutants of distinct C2 domains of dysferlin did not show this response.

129 Furthermore, dysferlin displayed significantly lower binding affinity

130 r the first time, to our knowledge, that all dysferlin domains bind Ca(2+) albeit with varying affini

131 To investigate the role of dysferlin during early muscle differentiation, its local

132 mic behavior and subcellular localization of dysferlin during membrane repair in adult skeletal muscl

133 adjacent sarcolemma to the repair patch in a Dysferlin (Dysf) dependent process in zebrafish and huma

134 Repair proteins, including dysferlin, EHD1, EHD2, MG53, and BIN1, localized adjacen

135 n levels in skeletal muscle, suggesting that dysferlin encoded by mis-sense alleles is rapidly degrad

136 Mice and patient lacking dysferlin exhibit chronic muscle inflammation and adipog

137 c inhibitors alters Fam65b expression, while dysferlin expression does not change.

138 y 2B and Miyoshi myopathy, which screens for dysferlin expression in blood using a commercially avail

139 siRNA-mediated inhibition of dysferlin expression in the J774 macrophage cell line re

140 essed in singly nucleated myoblasts, whereas dysferlin expression is increased in mature, multinuclea

141 Here we show that dysferlin expression is increased with differentiation i

142 ependent on membrane fusions mediated by the dysferlin FER-1.

143 to generate mice lacking both myoferlin and dysferlin (FER).

144 Dysferlin forms a protein complex with these integrins a

145 entified a highly reproducible jigsaw map of dysferlin fragments protected from digestion.

146 ar interactions and provide new insight into dysferlin function in inflammatory cells.

147 lta-sarcoglycan) null mouse, indicating that dysferlin functionality is not a limiting factor underly

148 Mutations in the dysferlin gene (DYSF) lead to human muscular dystrophies

149 In humans, mutations in the dysferlin gene are associated with muscular dystrophy.

150 Mutations in the dysferlin gene cause limb girdle muscular dystrophy 2B (

151 Mutations in the dysferlin gene cause limb girdle muscular dystrophy type

152 muscular dystrophies due to mutations in the dysferlin gene causing deficiency of a membrane-bound pr

153 The dysferlin gene is mutated in limb-girdle muscular dystro

154 Mutations in the dysferlin gene resulting in dysferlin-deficiency lead to

155 Mutations in the dysferlin gene underlie a group of autosomal recessive m

156 ntaneous myopathy and have a mutation in the dysferlin gene, a gene which is also mutated in human li

157 phy 2B (LGMD2B), caused by a mutation in the dysferlin gene.

158 lar dystrophy that arise from defects in the dysferlin gene.

159 , bearing a retrotransposon insertion in the dysferlin gene.

160 ce were located at the 3' and 5' ends of the dysferlin gene.

161 llelic disorders arising from defects in the dysferlin gene.

162 ave been associated with mutations in titin, dysferlin, GNE, desmin and myosin.

163 ctive process in skeletal muscle fibres, and dysferlin has an essential role in this process.

164 The precise role of dysferlin has been debated, partly because of the mild p

165 s in dysferlin cause muscular dystrophy, and dysferlin has been implicated in resealing membrane disr

166 Beyond membrane repair, dysferlin has been linked to SNARE-mediated exocytotic e

167 Dysferlin has been proposed as a critical regulator of v

168 Dysferlin has been shown to play roles in muscle membran

169 Studies of dysferlin have focused on its role in the repair of the

170 sensitive, the Ca(2+) binding properties of dysferlin have not been characterized.

171 We reasoned that mis-sense mutated dysferlin, if salvaged from degradation, might be biolog

172 result in aberrant localization of MG53 and dysferlin in a dominant-negative fashion, leading to def

173 cytes was confirmed, and a possible role for dysferlin in adipocytes is suggested.

174 s, annexins A1 and A2, and define a role for dysferlin in Ca2+-dependent repair of sarcolemmal injury

175 Local expression of dysferlin in dysferlin-null myofibres increases transien

176 To assess the function of dysferlin in healthy and dystrophic skeletal muscle, we

177 al muscle, little is known about the role of dysferlin in maintenance of cardiomyocytes.

178 ng the functional interplay between Cav3 and dysferlin in membrane repair of muscle physiology and di

179 These data implicate dysferlin in multiple membrane fusion events within the

180 s of muscle function, we studied the role of dysferlin in muscle growth.

181 ibres and therefore investigated the role of dysferlin in muscle regeneration.

182 In summary, the restoration of dysferlin in skeletal muscle fibers is sufficient to res

183 Our study links calpain and dysferlin in the calcium-activated vesicle fusion of mem

184 wever, neither the morphological location of dysferlin in the cardiomyocyte nor the progression of th

185 nd muscle necrosis; however, the function of dysferlin in the heart remains to be determined.

186 Recent work suggests a critical role for dysferlin in the membrane repair process and that mutati

187 are highly indicative of a specific role of dysferlin in this process in early myogenesis.

188 h is recapitulated by transient knockdown of dysferlin in THP1 cells.

189 er sarcolemmal damage involves dysferlin and dysferlin-interacting proteins such as annexins.

190 Dysferlin interacts with a new membrane repair protein,

191 Dysferlin is a Ca(2+)-sensing, regulatory protein that i

192 Dysferlin is a calcium-binding transmembrane protein inv

193 Dysferlin is a cell membrane bound protein with a role i

194 Dysferlin is a component of that system and absence of d

195 Dysferlin is a homologue of the Caenorhabditis elegans f

196 Dysferlin is a large membrane protein involved in calciu

197 Dysferlin is a large transmembrane protein composed of a

198 Dysferlin is a large transmembrane protein that plays a

199 Dysferlin is a membrane associated protein involved in v

200 Dysferlin is a membrane-associated protein implicated in

201 Dysferlin is a membrane-associated protein implicated in

202 n is highly homologous to dysferlin and like dysferlin is a plasma membrane protein with six C2 domai

203 Dysferlin is a transmembrane protein implicated in surfa

204 Calpain cleavage of dysferlin is a ubiquitous response to membrane injury in

205 Recent studies show that dysferlin is also expressed in monocytes.

206 Here, we demonstrate that dysferlin is also involved in cardiomyocyte membrane rep

207 ng patch repair vesicles with the sarcolemma dysferlin is also involved in the release of chemotactic

208 Although it is generally accepted that dysferlin is Ca(2+) sensitive, the Ca(2+) binding proper

209 These results suggest that dysferlin is critical for normal endocytosis during ooge

210 show that endogenous R555W mis-sense mutated dysferlin is degraded by the proteasomal system.

211 Here, we reveal that dysferlin is enriched in the t-tubule membrane of mature

212 is widely recognized in dysferlinopathy and dysferlin is expressed in immune cells, the contribution

213 adult dysf-pHGFP muscle fibers revealed that dysferlin is highly enriched in the sarcolemma and trans

214 GF receptor and transferrin, indicating that dysferlin is important for nonmuscle vesicular trafficki

215 These findings suggest that dysferlin is involved in regulating cellular interaction

216 In cardiac muscle, dysferlin is located at the intercalated disc and transv

217 In mature skeletal muscle, dysferlin is located predominantly at the sarcolemma, wh

218 re we show that injury-activated cleavage of dysferlin is mediated by the ubiquitous calpains via a c

219 Dysferlin is mutated in a group of muscular dystrophies

220 We determined that dysferlin is normally localized to the intercalated disk

221 This demonstrated that dysferlin is not expressed at the plasmalemma of myotube

222 Dysferlin is proposed as a key mediator of calcium-depen

223 in exists as long and short splice isoforms, dysferlin is subject to enzymatic cleavage releasing a s

224 The tricomplex Fam65b-HDAC6-dysferlin is transient, and Fam65b expression is necessa

225 we studied cardiac phenotypes of young adult dysferlin knockout mice and found early myocardial hyper

226 Here, we show that similar to dysferlin, lack of annexin A2 (AnxA2) also results in po

227 Recessive loss-of-function mutations in dysferlin lead to muscular dystrophies, for which no tre

228 Injection of a morpholino against dysferlin leads to a decrease of endocytosis in oocytes,

229 ore, a combined deficiency of dystrophin and dysferlin leads to early onset cardiomyopathy.

230 Deficiency of dysferlin leads to limb-girdle muscular dystrophy 2B (LG

231 in implicated in membrane resealing; loss of dysferlin leads to muscular dystrophy.

232 atients have significantly reduced or absent dysferlin levels in skeletal muscle, suggesting that dys

233 In the C57BL/6J background, dysferlin loss was associated with enhanced pathologic s

234 em C2 domains separated by linkers, suggests dysferlin may dynamically associate with phospholipid me

235 has inspired the hypothesis that ANO5, like dysferlin, may be involved in the repair of muscle membr

236 Our results suggest that dysferlin-mediated membrane repair is important for main

237 r extent, the C2D domain are dispensable for dysferlin membrane repair function.

238 utic strategy for patients harboring certain dysferlin mis-sense mutations.

239 s, limb-girdle muscular dystrophy 2L and non-dysferlin Miyoshi muscular dystrophy.

240 Our data suggest that dysferlin modulates SR Ca(2+) release in skeletal muscle

241 To design mini-dysferlin molecules suitable for AAV-mediated gene trans

242 he basis of these results, we designed small dysferlin molecules that can localize to the plasma memb

243 ized by massive immune cell infiltrates, and dysferlin-negative monocytes were shown to be more aggre

244 ile muscle-specific transgenic expression of dysferlin normalized the expression of complement factor

245 ce lifetime imaging microscopy revealed that dysferlin normally associates with both annexins A1 and

246 We also noted that dysferlin null fibroblasts also accumulate acidic vesicl

247 We found that myoblasts isolated from dysferlin null mice accumulate enlarged, lysosomal-assoc

248 In vivo, dysferlin null muscle was found to have mislocalized nuc

249 yofiber diameter by 30% as expected, whereas dysferlin null muscles had no response to IGF1, indicati

250 Dysferlin null myoblasts accumulate transferrin-488, ref

251 Additionally, dysferlin null myoblasts display abnormal trafficking of

252 We found that dysferlin null myoblasts have a defect in myoblast-myotu

253 oltage-induced Ca(2+) transients elicited in dysferlin-null A/J myofibres were smaller than control A

254 ted, partly because of the mild phenotype in dysferlin-null mice (Dysf).

255 ercise disturbs left ventricular function in dysferlin-null mice and increases Evans blue dye uptake

256 Here we show that dysferlin-null mice maintain a functional dystrophin-gly

257 iminated the dystrophic phenotype present in dysferlin-null mice.

258 sub-sarcolemmal accumulations of vesicles in dysferlin-null muscle.

259 Local expression of dysferlin in dysferlin-null myofibres increases transient amplitude t

260 Together, the data indicate that dysferlin, otoferlin, and myoferlin do not merely passiv

261 on structure of the inner DysF domain of the dysferlin paralogue myoferlin, which has a unique fold h

262 his issue of the JCI, Han et al. report that dysferlin participates in membrane resealing in cardiomy

263 A dysferlin-pHluorin [dysf-pH-sensitive green fluorescent

264 The large size of dysferlin precludes its encapsulation into an adeno-asso

265 es Ca(2+) leak) or local expression of Venus-dysferlin prevented OSI-induced Ca(2+) waves.

266 We conclude that dysferlin prevents injury-induced SR Ca(2+) leak.

267 tation or genetic disruption of myoferlin or dysferlin promotes muscular dystrophy-related phenotypes

268 We measured dysferlin protein and mRNA levels, resealing kinetics of

269 m65b is important for formation of the HDAC6-dysferlin protein complex during myogenic cell different

270 However, the overall conformation of the dysferlin protein is uncharacterized.

271 A deficiency of the dysferlin protein results in limb girdle muscular dystro

272 racterized by absence or marked reduction of dysferlin protein with 43% of reported pathogenic varian

273 Using five antibodies spanning the dysferlin protein, we identified a highly reproducible j

274 issense variants that span the length of the dysferlin protein.

275 uman myotubes, we show it is not full-length dysferlin recruited to sites of membrane injury but an i

276 Myoferlin and dysferlin regulate myoblast fusion and muscle membrane r

277 However, it is unclear whether dysferlin regulates SNARE-mediated membrane fusion.

278 Defects in dysferlin result in limb-girdle muscular dystrophy type

279 earned that in the sea star Patiria miniata, dysferlin RNA and protein are expressed from oogenesis t

280 thus both proteins play a role in injury in dysferlin's absence.

281 ir of the sarcolemma of skeletal muscle, but dysferlin's association with calcium (Ca(2+)) signaling

282 The full-length dysferlin sequence is highly conserved between human and

283 of decay accelerating factor, which was not dysferlin-specific.

284 seful model for studying the relationship of dysferlin structure as it relates to its function.

285 Dysferlin-sufficient A/WySnJ mice show much less myofibe

286 model of muscle membrane healing mediated by dysferlin that is relevant to both normal and dystrophic

287 The protein dysferlin, the product of the Limb Girdle Muscular Dystr

288 KEY POINTS: Dysferlin, the protein missing in limb girdle muscular d

289 Fam65b binds to HDAC6 and dysferlin, the protein mutated in limb girdle muscular d

290 decreased recruitment of sarcolemma-derived dysferlin to lesions in dysf-pHGFP fibers without affect

291 led that membrane injury induces cleavage of dysferlin to release a synaptotagmin-like C-terminal mod

292 e sarcolemma and is required for movement of dysferlin to sites of cell injury during repair patch fo

293 The dysferlin transgene rescued all histopathology and macro

294 However, dysferlin translocated to the site of injury and toward

295 n the gene DYSF, which codes for the protein dysferlin, underlie Miyoshi myopathy and limb-girdle mus

296 opathy were directly mediated by the loss of dysferlin via a new pathogenic mechanism in muscular dys

297 Like dysferlin, we found that myoferlin binds phospholipids i

298 To dissect the structural architecture of dysferlin, we have applied the method of limited proteol

299 Because monocytes normally express dysferlin, we hypothesized that monocyte/macrophage dysf

300 The unique structure of dysferlin, with seven tandem C2 domains separated by lin