Identical dysferlin mutation in limb-girdle muscular dystrophy type 2B and distal myopathy

Иллариошкин, С. Н.; Ivanova-Smolenskaya, I. A.; Greenberg, Cheryl R.; Nylen, Edward; Сухоруков, В. С.; Полещук, В.В.; Markova, E D; Wrogemann, Klaus

doi:10.1212/wnl.55.12.1931

Cited by 113 publications

(96 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…V67D mutation in dysferlin C2A abolishes phospholipid binding. A point mutation in dysferlin (V67D) was described as being associated with muscular dystrophy (31). Dysferlin C2A was expressed as a GST fusion protein and purified from E. coli.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Calcium-sensitive Phospholipid Binding Properties of Normal and Mutant Ferlin C2 Domains

Davis¹,

Doherty²,

Delmonte³

et al. 2002

Journal of Biological Chemistry

180

190

View full text Add to dashboard Cite

Mutations in dysferlin, a novel membrane protein of unknown function, lead to muscular dystrophy. Myoferlin is highly homologous to dysferlin and like dysferlin is a plasma membrane protein with six C2 domains highly expressed in muscle. C2 domains are found in a variety of membrane-associated proteins where they have been implicated in calcium, phospholipid, and protein-binding. We investigated the pattern of dysferlin and myoferlin expression in a cell culture model of muscle development and found that dysferlin is expressed in mature myotubes. In contrast, myoferlin is highly expressed in elongated "prefusion" myoblasts and is decreased in mature myotubes where dysferlin expression is greatest. We tested ferlin C2 domains for their ability to bind phospholipid in a calcium-sensitive manner. We found that C2A, the first C2 domain of dysferlin and myoferlin, bound 50% phosphatidylserine and that phospholipid binding was regulated by calcium concentration. A dysferlin point mutation responsible for muscular dystrophy was engineered into the dysferlin C2A domain and demonstrated reduced calcium-sensitive phospholipid binding. Based on these data, we propose a mechanism for muscular dystrophy in which calcium-regulated phospholipid binding is abnormal, leading to defective maintenance and repair of muscle membranes.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Illarioshkin et al (31) described a mutation associated with both mild and severe phenotypes that changed a single amino acid (V67D) within the C2A domain of dysferlin. This amino acid substitution occurs within one of the eight ␤ strands and inserts a novel charge residue.…”

Section: Discussionmentioning

confidence: 99%

Calcium-sensitive Phospholipid Binding Properties of Normal and Mutant Ferlin C2 Domains

Davis¹,

Doherty²,

Delmonte³

et al. 2002

Journal of Biological Chemistry

180

190

View full text Add to dashboard Cite

show abstract

“…Mutations within a critical membrane repair protein, dysferlin, lead to two mild but progressive forms of muscular dystrophy termed limb-girdle muscular dystrophy 2B (LGMD2B) and Myoshi myopathy (MM) (4,5). Dysferlin is a single-pass transmembrane protein containing multiple cytoplasmic C2 domains, and is a member of the evolutionarily conserved ferlin family of proteins.…”

Section: Introductionmentioning

confidence: 99%

Membrane damage-induced vesicle–vesicle fusion of dysferlin-containing vesicles in muscle cells requires microtubules and kinesin

McDade

Michele

2013

Human Molecular Genetics

View full text Add to dashboard Cite

Mutations in the dysferlin gene resulting in dysferlin-deficiency lead to limb-girdle muscular dystrophy 2B and Myoshi myopathy in humans. Dysferlin has been proposed as a critical regulator of vesicle-mediated membrane resealing in muscle fibers, and localizes to muscle fiber wounds following sarcolemma damage. Studies in fibroblasts and urchin eggs suggest that trafficking and fusion of intracellular vesicles with the plasma membrane during resealing requires the intracellular cytoskeleton. However, the contribution of dysferlin-containing vesicles to resealing in muscle and the role of the cytoskeleton in regulating dysferlin-containing vesicle biology is unclear. Here, we use live-cell imaging to examine the behavior of dysferlin-containing vesicles following cellular wounding in muscle cells and examine the role of microtubules and kinesin in dysferlin-containing vesicle behavior following wounding. Our data indicate that dysferlin-containing vesicles move along microtubules via the kinesin motor KIF5B in muscle cells. Membrane wounding induces dysferlin-containing vesicle-vesicle fusion and the formation of extremely large cytoplasmic vesicles, and this response depends on both microtubules and functional KIF5B. In non-muscle cell types, lysosomes are critical mediators of membrane resealing, and our data indicate that dysferlincontaining vesicles are capable of fusing with lysosomes following wounding which may contribute to formation of large wound sealing vesicles in muscle cells. Overall, our data provide mechanistic evidence that microtubulebased transport of dysferlin-containing vesicles may be critical for resealing, and highlight a critical role for dysferlin-containing vesicle-vesicle and vesicle-organelle fusion in response to wounding in muscle cells.

show abstract

“…Dysferlin-mediated muscular dystrophy is associated with the sub-plasmalemmal accumulation of vesicles (Cenacchi et al, 2005;Piccolo et al, 2000). A missense mutation in the C2A of dysferlin, V67D, is responsible for muscular dystrophy (Illarioshkin et al, 2000), and abolishes C2A calcium-induced phospholipid binding in vitro (Davis et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Normal myoblast fusion requires myoferlin

et al. 2005

View full text Add to dashboard Cite

Muscle growth occurs during embryonic development and continues in adult life as regeneration. During embryonic muscle growth and regeneration in mature muscle, singly nucleated myoblasts fuse to each other to form myotubes. In muscle growth, singly nucleated myoblasts can also fuse to existing large,syncytial myofibers as a mechanism of increasing muscle mass without increasing myofiber number. Myoblast fusion requires the alignment and fusion of two apposed lipid bilayers. The repair of muscle plasma membrane disruptions also relies on the fusion of two apposed lipid bilayers. The protein dysferlin, the product of the Limb Girdle Muscular Dystrophy type 2 locus, has been shown to be necessary for efficient, calcium-sensitive,membrane resealing. We now show that the related protein myoferlin is highly expressed in myoblasts undergoing fusion, and is expressed at the site of myoblasts fusing to myotubes. Like dysferlin, we found that myoferlin binds phospholipids in a calcium-sensitive manner that requires the first C2A domain. We generated mice with a null allele of myoferlin. Myoferlin null myoblasts undergo initial fusion events, but they form large myotubes less efficiently in vitro, consistent with a defect in a later stage of myogenesis. In vivo, myoferlin null mice have smaller muscles than controls do, and myoferlin null muscle lacks large diameter myofibers. Additionally, myoferlin null muscle does not regenerate as well as wild-type muscle does, and instead displays a dystrophic phenotype. These data support a role for myoferlin in the maturation of myotubes and the formation of large myotubes that arise from the fusion of myoblasts to multinucleate myotubes.

show abstract

Identical dysferlin mutation in limb-girdle muscular dystrophy type 2B and distal myopathy

Cited by 113 publications

References 9 publications

Calcium-sensitive Phospholipid Binding Properties of Normal and Mutant Ferlin C2 Domains

Calcium-sensitive Phospholipid Binding Properties of Normal and Mutant Ferlin C2 Domains

Membrane damage-induced vesicle–vesicle fusion of dysferlin-containing vesicles in muscle cells requires microtubules and kinesin

Normal myoblast fusion requires myoferlin

Contact Info

Product

Resources

About