Sub-cellular localisation of fukutin related protein in different cell lines and in the muscle of patients with MDC1C and LGMD2I

Torelli, Silvia; Brown, Susan C.; Brockington, M; Dolatshad, Nazanin F.; Jimenez, Cecilia; Skordis, L.; Feng, Lucy; Merlini, Luciano; Romero, Norma B.; Wewer, Ulla M.; Voït, Thomas; Sewry, Caroline A.; Noguchi, S.; Nishino, Ichizo; Muntoni, Francesco

doi:10.1016/j.nmd.2005.09.004

Cited by 30 publications

(33 citation statements)

References 31 publications

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“…We have likewise observed perinuclear staining of recombinant and native FKRP in various cultured cells using the FKRP C-terminal antibody described here (data not shown). In muscle sections, FKRP signal was reported to be perinuclear (possibly rough ER) or concentrated to granular structures inside muscle fibers (7,9,11). Although our data conflict with these previous findings, the fact that we detected sarcolemmal staining of native FKRP with antibodies directed against two distinct FKRP epitopes and confirmed membrane localization of FKRP (but not fukutin) using recombinant fusion proteins provides strong support for the targeting of FKRP to the sarcolemma.…”

Section: Discussioncontrasting

confidence: 88%

“…Previous studies have suggested that FKRP expression is restricted to Golgi, perinuclear, or rough endoplasmic reticulum domains, although most of this work was done in cultured cells and may be subject to limitations of such in vitro systems (7)(8)(9)(10)(11). We have likewise observed perinuclear staining of recombinant and native FKRP in various cultured cells using the FKRP C-terminal antibody described here (data not shown).…”

Section: Discussionsupporting

confidence: 65%

“…COS7, SH-SY5Y, C2C12). The variable results suggested that FKRP is a resident of the Golgi, the rough endoplasmic reticulum, or perinuclear regions (7)(8)(9)(10)(11). In this study, we have examined FKRP protein complexes and their location in skeletal muscle of wild-type and dystrophic mice.…”

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confidence: 99%

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Fukutin-related Protein Associates with the Sarcolemmal Dystrophin-Glycoprotein Complex

Beedle

Nienaber

Campbell

2007

Journal of Biological Chemistry

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Mutations in fukutin-related protein (FKRP) give rise to mild and more severe forms of muscular dystrophy. FKRP patients have reduced glycosylation of the extracellular protein dystroglycan, and FKRP itself shows sequence similarity to glycosyltransferases, implicating FKRP in the processing of dystroglycan. However, FKRP localization is controversial, and no FKRP complexes are known, so any FKRP-dystroglycan link remains elusive. Here, we demonstrate a novel FKRP localization in vivo; in mouse, both endogenous and recombinant FKRP are present at the sarcolemma. Biochemical analyses revealed that mouse muscle FKRP and dystroglycan co-enrich and co-fractionate, indicating that FKRP coexists with dystroglycan in the native dystrophin-glycoprotein complex. Furthermore, FKRP sedimentation shifts with dystroglycan in disease models involving the dystrophin-glycoprotein complex, and sarcolemmal FKRP immunofluorescence mirrors that of dystroglycan in muscular dystrophy mice, suggesting that FKRP localization may be mediated by dystroglycan. These data offer the first evidence of an FKRP complex in muscle and suggest that FKRP may influence the glycosylation status of dystroglycan from within the sarcolemmal dystrophin-glycoprotein complex. Mutations in FKRP3 lead to the allelic muscular dystrophies, congenital muscular dystrophy 1C and limb girdle muscular dystrophy 2I, characterized by progressive muscle weakness with variable heart, respiratory, and brain involvement (1-3). Although the specific function of FKRP is unclear, FKRP and its closest known homolog fukutin share sequence homology with phosphoryl ligand transferases and contain DXD domains common to some glycosyltransferases (4, 5). In addition, FKRPassociated muscular dystrophies fall into a growing family of "dystroglycanopathies," which exhibit reduced glycosylation of membrane-associated ␣DG (6). Extracellular ␣DG and the transmembrane-spanning ␤DG bind to dystrophin, sarcoglycans, and other proteins to form the dystrophin-glycoprotein complex (DGC), which serves as a critical structural link between the cell cytoskeleton, the sarcolemma, and the extracellular basement membrane. ␣DG glycans, detected by antibody IIH6, mediate the interaction between the DGC and extracellular matrix proteins that contain laminin LG domains. Therefore, reduced ␣DG glycosylation may weaken the cell to matrix link, increasing structural instability and disease (6).Previous studies have examined the localization of FKRP in a spectrum of cultured cells (e.g. COS7, SH-SY5Y, C2C12). The variable results suggested that FKRP is a resident of the Golgi, the rough endoplasmic reticulum, or perinuclear regions (7-11). In this study, we have examined FKRP protein complexes and their location in skeletal muscle of wild-type and dystrophic mice. We report that FKRP is localized at the muscle sarcolemma and that it co-fractionates with the DGC. Furthermore, disruption of the DGC (by alkaline treatment or genetic deletion) revealed that FKRP sedimentation and localization are dependent on...

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Section: Discussioncontrasting

confidence: 88%

Section: Discussionsupporting

confidence: 65%

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Fukutin-related Protein Associates with the Sarcolemmal Dystrophin-Glycoprotein Complex

Beedle

Nienaber

Campbell

2007

Journal of Biological Chemistry

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“…FKRP has been localized to the Golgi apparatus in neuroblastoma, oligodendroglial and cardiac muscle cell lines, and shows the same intracellular distribution in skeletal muscle tissue taken from control, MDC1C and LGMD2I patients. 54 Muntoni and colleagues have shown a correlation between the extent of dystroglycan underglycosylation in MDC1C and LGMD2I and the clinical phenotype, the L276I mutation being the least severe on both fronts. 55 Therefore, underglycosylation of α-dystroglycan appears to be the causative factor in all of these disorders.…”

Section: Dystroglycanopathy-gene Function: Some Mysteries Remainmentioning

confidence: 99%

Mechanisms of Disease: congenital muscular dystrophies—glycosylation takes center stage

Martin

2006

Nat Rev Neurol

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SUMMARYRecent studies have defined a group of muscular dystrophies, now termed the dystroglycanopathies, as novel disorders of glycosylation. These conditions include Walker-Warburg syndrome, muscleeye-brain disease, Fukuyama-type congenital muscular dystrophy, congenital muscular dystrophy types 1C and 1D, and limb-girdle muscular dystrophy type 2I. Although clinical findings can be highly variable, dystroglycanopathies are all characterized by cortical malformations and ocular defects at the more severe end of the clinical spectrum, in addition to muscular dystrophy. All of these disorders are defined by the underglycosylation of α-dystroglycan. Defective glycosylation of dystroglycan severs the link between this important cell adhesion molecule and the extracellular matrix, thereby contributing to cellular pathology. Recent experiments indicate that glycosylation might not only define forms of muscular dystrophy but also provide an avenue to the development of therapies for these disorders.

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“…However, when amalgamating these results, it remains clear that FKRP mutations are the most frequently found in this group of conditions. We and others have previously published extensively on the spectrum of these mutations (128,205,211,258,(262)(263)(264)(265)(266)(267)(268)(269)(270)(271). (Figure 12 and Table 10).…”

Section: Mutation Frequenciesmentioning

confidence: 99%

Congenital Muscular Dystrophy

Oh¹,

Park²,

Yun³

et al. 2012

Atlas of Genetic Diagnosis and Counseling

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The second part of the thesis is concerned with the dystroglycanopathies, a recently described group of CMDs associated with aberrant glycosylation of alpha dystroglycan.To date, 7 genes have been identified, some of which give rise to multiple dystroglycanopathy phenotypes. I studied the genotype-phenotype relationship in a large group of dystroglycanopathy patients, reporting new clinical phenotypes and establishing the mutation frequency in this group. I also report in detail the spectrum of MRI brain changes seen in 27 dystroglycanopathy patients.In summary, this work reports the diagnostic outcome in the largest cohort of UK CMD cases studied and refines the genotype-phenotype correlation in patients with dystroglycanopathies.

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Sub-cellular localisation of fukutin related protein in different cell lines and in the muscle of patients with MDC1C and LGMD2I

Cited by 30 publications

References 31 publications

Fukutin-related Protein Associates with the Sarcolemmal Dystrophin-Glycoprotein Complex

Fukutin-related Protein Associates with the Sarcolemmal Dystrophin-Glycoprotein Complex

Mechanisms of Disease: congenital muscular dystrophies—glycosylation takes center stage

Congenital Muscular Dystrophy

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