The ties that bind: functional clusters in limb-girdle muscular dystrophy

Barton, Elisabeth R.; Pacak, Christina A.; Stoppel, Whitney L.; Kang, Peter B.

doi:10.1186/s13395-020-00240-7

Cited by 21 publications

(26 citation statements)

References 176 publications

(214 reference statements)

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“…The cellular localizations of most of the proteins are within the nucleus, sarcolemma, and cytosol, particularly the Golgi apparatus, endoplasmic reticulum (ER), and sarcomere (Fig. 1 ) [ 6 , 13 , 14 ]. Subcellular activities of the involved proteins can be categorized into three distinct functions: the glycosylation modification, mitochondrial dysfunction, and the mechanical signaling [ 6 ].…”

Section: Molecular Biology Of Lgmdmentioning

confidence: 99%

“…The third functional category for LGMD proteins involves mechanical perturbation in skeletal muscle cells and is related to changes in MAPK pathway phosphorylation [ 6 ]. This pathway is involved in the most prevalent subtypes of LGMD, including the proteins involved in the sarcoglycan complex (R3-R6).…”

Section: Molecular Biology Of Lgmdmentioning

confidence: 99%

“…Although multiple reviews exist that describe LGMD [ 1 – 3 , 6 , 9 – 12 ], this communication adds a holistic perspective of this family of diseases. This article surveys the genetic causation of the newly defined subtypes, which in turn affects the relevant proteins and their localization in muscle cells.…”

Section: Introductionmentioning

confidence: 99%

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A Journey with LGMD: From Protein Abnormalities to Patient Impact

Georganopoulou¹,

Moisiadis²,

Malik³

et al. 2021

Protein J

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The limb-girdle muscular dystrophies (LGMD) are a collection of genetic diseases united in their phenotypical expression of pelvic and shoulder area weakness and wasting. More than 30 subtypes have been identified, five dominant and 26 recessive. The increase in the characterization of new genotypes in the family of LGMDs further adds to the heterogeneity of the disease. Meanwhile, better understanding of the phenotype led to the reconsideration of the disease definition, which resulted in eight old subtypes to be no longer recognized officially as LGMD and five new diseases to be added to the LGMD family. The unique variabilities of LGMD stem from genetic mutations, which then lead to protein and ultimately muscle dysfunction. Herein, we review the LGMD pathway, starting with the genetic mutations that encode proteins involved in muscle maintenance and repair, and including the genotype–phenotype relationship of the disease, the epidemiology, disease progression, burden of illness, and emerging treatments.

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Section: Molecular Biology Of Lgmdmentioning

confidence: 99%

Section: Molecular Biology Of Lgmdmentioning

confidence: 99%

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A Journey with LGMD: From Protein Abnormalities to Patient Impact

Georganopoulou¹,

Moisiadis²,

Malik³

et al. 2021

Protein J

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“…LGMD is a highly diverse group of muscular dystrophies, which have been linked to a wide variety of proteins affecting glycosylation of dystroglycan, are involved in mechanical signaling (sarcoglycans) and in mitochondrial function [141]. Three genes, DYSF, ANO5 and CAV3 have been linked to LGMD and encode proteins, which have been found to interact with POPDC proteins [24,29,132].…”

Section: Mutations In Popdc Genes Are Causing Heart and Muscle Diseasementioning

confidence: 99%

The Role of POPDC Proteins in Cardiac Pacemaking and Conduction

Gruscheski

Brand

2021

JCDD

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The Popeye domain-containing (POPDC) gene family, consisting of Popdc1 (also known as Bves), Popdc2, and Popdc3, encodes transmembrane proteins abundantly expressed in striated muscle. POPDC proteins have recently been identified as cAMP effector proteins and have been proposed to be part of the protein network involved in cAMP signaling. However, their exact biochemical activity is presently poorly understood. Loss-of-function mutations in animal models causes abnormalities in skeletal muscle regeneration, conduction, and heart rate adaptation after stress. Likewise, patients carrying missense or nonsense mutations in POPDC genes have been associated with cardiac arrhythmias and limb-girdle muscular dystrophy. In this review, we introduce the POPDC protein family, and describe their structure function, and role in cAMP signaling. Furthermore, the pathological phenotypes observed in zebrafish and mouse models and the clinical and molecular pathologies in patients carrying POPDC mutations are described.

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“…The dystrophin glycoprotein complex (DGC) is a major sarcolemmal complex that tethers the extracellular matrix (ECM) to the intracellular actin cytoskeleton [ 1 , 2 ]. Together with the integrin-associated focal adhesion complex [ 3 , 4 ], the DGC stabilizes the membrane, senses mechanical stress, and transmits “outside-in” information to the nucleus via signaling proteins, including phosphorylated signaling kinases [ 5 , 6 ]. The dominant DGC connection to actin is via dystrophin, which links the actin cytoskeleton to dystroglycan, and in turn binds laminin in the ECM [ 1 , 2 ].…”

Section: Introductionmentioning

confidence: 99%

Novel γ-sarcoglycan interactors in murine muscle membranes

et al. 2022

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Background The sarcoglycan complex (SC) is part of a network that links the striated muscle cytoskeleton to the basal lamina across the sarcolemma. The SC coordinates changes in phosphorylation and Ca++-flux during mechanical deformation, and these processes are disrupted with loss-of-function mutations in gamma-sarcoglycan (Sgcg) that cause Limb girdle muscular dystrophy 2C/R5. Methods To gain insight into how the SC mediates mechano-signaling in muscle, we utilized LC-MS/MS proteomics of SC-associated proteins in immunoprecipitates from enriched sarcolemmal fractions. Criteria for inclusion were co-immunoprecipitation with anti-Sgcg from C57BL/6 control muscle and under-representation in parallel experiments with Sgcg-null muscle and with non-specific IgG. Validation of interaction was performed in co-expression experiments in human RH30 rhabdomyosarcoma cells. Results We identified 19 candidates as direct or indirect interactors for Sgcg, including the other 3 SC proteins. Novel potential interactors included protein-phosphatase-1-catalytic-subunit-beta (Ppp1cb, PP1b) and Na+-K+-Cl−-co-transporter NKCC1 (SLC12A2). NKCC1 co-localized with Sgcg after co-expression in human RH30 rhabdomyosarcoma cells, and its cytosolic domains depleted Sgcg from cell lysates upon immunoprecipitation and co-localized with Sgcg after detergent permeabilization. NKCC1 localized in proximity to the dystrophin complex at costameres in vivo. Bumetanide inhibition of NKCC1 cotransporter activity in isolated muscles reduced SC-dependent, strain-induced increases in phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). In silico analysis suggests that candidate SC interactors may cross-talk with survival signaling pathways, including p53, estrogen receptor, and TRIM25. Conclusions Results support that NKCC1 is a new SC-associated signaling protein. Moreover, the identities of other candidate SC interactors suggest ways by which the SC and NKCC1, along with other Sgcg interactors such as the membrane-cytoskeleton linker archvillin, may regulate kinase- and Ca++-mediated survival signaling in skeletal muscle.

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The ties that bind: functional clusters in limb-girdle muscular dystrophy

Cited by 21 publications

References 176 publications

A Journey with LGMD: From Protein Abnormalities to Patient Impact

A Journey with LGMD: From Protein Abnormalities to Patient Impact

The Role of POPDC Proteins in Cardiac Pacemaking and Conduction

Novel γ-sarcoglycan interactors in murine muscle membranes

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