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fukutin related protein

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https://www.readbyqxmd.com/read/29081423/muscular-dystrophy-with-ribitol-phosphate-deficiency-a-novel-post-translational-mechanism-in-dystroglycanopathy
#1
Motoi Kanagawa, Tatsushi Toda
Muscular dystrophy is a group of genetic disorders characterized by progressive muscle weakness. In the early 2000s, a new classification of muscular dystrophy, dystroglycanopathy, was established. Dystroglycanopathy often associates with abnormalities in the central nervous system. Currently, at least eighteen genes have been identified that are responsible for dystroglycanopathy, and despite its genetic heterogeneity, its common biochemical feature is abnormal glycosylation of alpha-dystroglycan. Abnormal glycosylation of alpha-dystroglycan reduces its binding activities to ligand proteins, including laminins...
October 24, 2017: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/28931339/limb-girdle-muscular-dystrophy-type-2i-two-chinese-families-and-a-review-in-asian-patients
#2
Dan-Ni Wang, Zhi-Qiang Wang, Yu-Qing Chen, Guo-Rong Xu, Min-Ting Lin, Ning Wang
BACKGROUND: Limb-girdle muscular dystrophy type 2I (LGMD2I) is an autosomal recessive hereditary disorder caused by mutations in the fukutin-related protein (FKRP) gene. Although the features of the disorder in European patients have been summarized, Asian patients with LGMD2I have rarely been reported. Thus, the clinical differences in LGMD2I between Asian and European patients and the associated genetic changes remain unclear. METHODS: We reported detailed clinical data as well as results from muscle biopsy, muscle MRI and genetic analysis of the FKRP gene in two unrelated Chinese families with LGMD2I...
October 2, 2017: International Journal of Neuroscience
https://www.readbyqxmd.com/read/28860175/skeletal-muscle-contractile-properties-in-a-novel-murine-model-for-limb-girdle-muscular-dystrophy-2i
#3
Jordan D Rehwaldt, Buel D Rodgers, David C Lin
Limb-girdle muscular dystrophy (LGMD) 2i results from mutations in fukutin-related protein and aberrant α-dystroglycan glycosylation. Although this significantly compromises muscle function and ambulation, the comprehensive characteristics of contractile dysfunction are unknown. We therefore quantified the in situ contractile properties of the medial gastrocnemius in young adult P448L mice, an affected muscle and novel model of LGMD2i, respectively. Maximal twitch force, tetanic force and power normalized to physiological cross-sectional area were significantly smaller in P448L mice, compared to sex-matched wild-type mice...
August 31, 2017: Journal of Applied Physiology
https://www.readbyqxmd.com/read/28666318/autologous-intramuscular-transplantation-of-engineered-satellite-cells-induces-exosome-mediated-systemic-expression-of-fukutin-related-protein-and-rescues-disease-phenotype-in-a-murine-model-of-limb-girdle-muscular-dystrophy-type-2i
#4
Paola Frattini, Chiara Villa, Francesca De Santis, Mirella Meregalli, Marzia Belicchi, Silvia Erratico, Pamela Bella, Manuela Teresa Raimondi, Qilong Lu, Yvan Torrente
α-Dystroglycanopathies are a group of muscular dystrophies characterized by α-DG hypoglycosylation and reduced extracellular ligand-binding affinity. Among other genes involved in the α-DG glycosylation process, fukutin related protein (FKRP) gene mutations generate a wide range of pathologies from mild limb girdle muscular dystrophy 2I (LGMD2I), severe congenital muscular dystrophy 1C (MDC1C), to Walker-Warburg Syndrome and Muscle-Eye-Brain disease. FKRP gene encodes for a glycosyltransferase that in vivo transfers a ribitol phosphate group from a CDP -ribitol present in muscles to α-DG, while in vitro it can be secreted as monomer of 60kDa...
October 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28663375/sexually-dimorphic-skeletal-muscle-and-cardiac-dysfunction-in-a-mouse-model-of-limb-girdle-muscular-dystrophy-2i
#5
Joseph W Maricelli, Denali R Kagel, Yemeserach M Bishaw, O Lynne Nelson, David C Lin, Buel D Rodgers
The fukutin-related protein P448L mutant mouse replicates pathologies common to limb-girdle muscular dystrophy 2i (LGMD2i) and is a strong candidate for relevant drug screening studies. Because striated muscle function remains relatively uncharacterized in this mouse, we sought to identify metabolic, functional and histological metrics of exercise and cardiac performance by quantifying voluntary exercise on running wheels, forced exercise on respiratory treadmills and cardiac output with echocardiography and isoproterenol stress tests...
June 29, 2017: Journal of Applied Physiology
https://www.readbyqxmd.com/read/28480302/efficacy-of-gene-therapy-is-dependent-on-disease-progression-in-dystrophic-mice-with-mutations-in-the-fkrp-gene
#6
Charles Harvey Vannoy, Will Xiao, Peijuan Lu, Xiao Xiao, Qi Long Lu
Loss-of-function mutations in the Fukutin-related protein (FKRP) gene cause limb-girdle muscular dystrophy type 2I (LGMD2I) and other forms of congenital muscular dystrophy-dystroglycanopathy that are associated with glycosylation defects in the α-dystroglycan (α-DG) protein. Systemic administration of a single dose of recombinant adeno-associated virus serotype 9 (AAV9) vector expressing human FKRP to a mouse model of LGMD2I at various stages of disease progression was evaluated. The results demonstrate rescue of functional glycosylation of α-DG and muscle function, along with improvements in muscle structure at all disease stages versus age-matched untreated cohorts...
June 16, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28479227/limb-girdle-muscular-dystrophy-type-2i-no-correlation-between-clinical-severity-histopathology-and-glycosylated-%C3%AE-dystroglycan-levels-in-patients-homozygous-for-common-fkrp-mutation
#7
Maisoon Alhamidi, Vigdis Brox, Eva Stensland, Merete Liset, Sigurd Lindal, Øivind Nilssen
Limb girdle muscular dystrophy type 2I (LGMD2I) is a progressive disorder caused by mutations in the FuKutin-Related Protein gene (FKRP). LGMD2I displays clinical heterogeneity with onset of severe symptoms in early childhood to mild calf and thigh hypertrophy in the second or third decade. Patients homozygous for the common FKRP mutation c.826C>A (p.Leu276Ile) show phenotypes within the milder end of the clinical spectrum. However, this group also manifests substantial clinical variability. FKRP deficiency causes hypoglycosylation of α-dystroglycan; a component of the dystrophin associated glycoprotein complex...
July 2017: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/28334834/aav-mediated-transfer-of-fkrp-shows-therapeutic-efficacy-in-a-murine-model-but-requires-control-of-gene-expression
#8
Evelyne Gicquel, Natacha Maizonnier, Steven J Foltz, William J Martin, Nathalie Bourg, Fedor Svinartchouk, Karine Charton, Aaron M Beedle, Isabelle Richard
Limb Girdle Muscular Dystrophies type 2I (LGMD2I), a recessive autosomal muscular dystrophy, is caused by mutations in the Fukutin Related Protein (FKRP) gene. It has been proposed that FKRP, a ribitol-5-phosphate transferase, is a participant in α-dystroglycan (αDG) glycosylation, which is important to ensure the cell/matrix anchor of muscle fibers. A LGMD2I knock-in mouse model was generated to express the most frequent mutation (L276I) encountered in patients. The expression of FKRP was not altered neither at transcriptional nor at translational levels, but its function was impacted since abnormal glycosylation of αDG was observed...
May 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28112097/a-novel-fkrp-related-muscular-dystrophy-founder-mutation-in-south-african-afrikaner-patients-with-a-phenotype-suggestive-of-a-dystrophinopathy
#9
M M Mudau, F Essop, A Krause
BACKGROUND: Fukutin-related protein (FKRP) muscular dystrophy is an autosomal recessive disorder caused by mutations in the FKRP gene. The condition is often misdiagnosed as a dystrophinopathy. A previously unreported mutation, c.1100T>C in exon 4 of FKRP, had been identified in homozygous form in two white South African (SA) Afrikaner patients clinically diagnosed with a dystrophinopathy. OBJECTIVES: To investigate whether the c.1100T>C mutation and the common European FKRP mutation c...
December 21, 2016: South African Medical Journal, Suid-Afrikaanse Tydskrif Vir Geneeskunde
https://www.readbyqxmd.com/read/28039900/evidence-of-early-defects-in-cajal-retzius-cell-localization-during-brain-development-in-a-mouse-model-of-dystroglycanopathy
#10
H S Booler, V Pagalday-Vergara, J L Williams, M Hopkinson, S C Brown
AIMS: The secondary dystroglycanopathies represent a heterogeneous group of congenital muscular dystrophies characterized by the defective glycosylation of alpha dystroglycan. These disorders are associated with mutations in at least 17 genes, including Fukutin-related protein (FKRP). At the severe end of the clinical spectrum there is substantial brain involvement, and cobblestone lissencephaly is highly suggestive of these disorders. The precise pathogenesis of this phenotype has, however, remained unclear with most attention focused on the disruption to the radial glial scaffold...
June 2017: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/27906078/four-week-rapamycin-treatment-improves-muscular-dystrophy-in-a-fukutin-deficient-mouse-model-of-dystroglycanopathy
#11
Steven J Foltz, Junna Luan, Jarrod A Call, Ankit Patel, Kristen B Peissig, Marisa J Fortunato, Aaron M Beedle
BACKGROUND: Secondary dystroglycanopathies are a subset of muscular dystrophy caused by abnormal glycosylation of α-dystroglycan (αDG). Loss of αDG functional glycosylation prevents it from binding to laminin and other extracellular matrix receptors, causing muscular dystrophy. Mutations in a number of genes, including FKTN (fukutin), disrupt αDG glycosylation. METHODS: We analyzed conditional Fktn knockout (Fktn KO) muscle for levels of mTOR signaling pathway proteins by Western blot...
June 2, 2016: Skeletal Muscle
https://www.readbyqxmd.com/read/27872178/childhood-activity-on-progression-in-limb-girdle-muscular-dystrophy-2i
#12
Brianna N Brun, Shelley R H Mockler, Katie M Laubscher, Carrie M Stephan, Julia A Collison, M Bridget Zimmerman, Katherine D Mathews
Limb girdle muscular dystrophy 2I is a slowly progressive muscular dystrophy due to mutations in the Fukutin-related protein ( FKRP) gene. Clinicians are frequently asked if physical activity is harmful for pediatric patients with limb girdle muscular dystrophy 2I. The primary objective of this study was to determine if there is a relationship between self-reported childhood activity level and motor function and respiratory function in older children and adults with limb girdle muscular dystrophy 2I. We compared retrospective self-reported middle school activity level and sport participation with age at onset of weakness, 10-meter walk test, and forced vital capacity later in life in 41 participants with FKRP mutations...
February 2017: Journal of Child Neurology
https://www.readbyqxmd.com/read/27711214/progressive-dystrophic-pathology-in-diaphragm-and-impairment-of-cardiac-function-in-fkrp-p448l-mutant-mice
#13
Anthony Blaeser, Hiroyuki Awano, Bo Wu, Qi-Long Lu
Mutations in the gene for fukutin-related protein represent a subset of muscular dystrophies known as dystroglycanopathies characterized by loss of functionally-glycosylated-alpha-dystroglycan and a wide range of dystrophic phenotypes. Mice generated by our lab containing the P448L mutation in the fukutin-related protein gene demonstrate the dystrophic phenotype similar to that of LGMD2I. Here we examined the morphology of the heart and diaphragm, focusing on pathology of diaphragm and cardiac function of the mutant mice for up to 12 months...
2016: PloS One
https://www.readbyqxmd.com/read/27627455/trendelenburg-like-gait-instability-and-altered-step-patterns-in-a-mouse-model-for-limb-girdle-muscular-dystrophy-2i
#14
Joseph W Maricelli, Qi L Lu, David C Lin, Buel D Rodgers
Limb-girdle muscular dystrophy type 2i (LGMD2i) affects thousands of lives with shortened life expectancy mainly due to cardiac and respiratory problems and difficulty with ambulation significantly compromising quality of life. Limited studies have noted impaired gait in patients and animal models of different muscular dystrophies, but not in animal models of LGMD2i. Our goal, therefore, was to quantify gait metrics in the fukutin-related protein P448L mutant (P448L) mouse, a recently developed model for LGMD2i...
2016: PloS One
https://www.readbyqxmd.com/read/27515093/expression-of-glycosylated-%C3%AE-dystroglycan-in-newborn-skeletal-and-cardiac-muscles-of-fukutin-related-protein-fkrp-mutant-mice
#15
Elizabeth Keramaris, Pei J Lu, Jason Tucker, Qi L Lu
INTRODUCTION: Mutations in the Fukutin related protein (FKRP) gene are characterized by a lack of functionally glycosylated α-dystroglycan (F-α-DG) in muscles. A small number of fibers retain the capacity to produce strong IIH6 reactive glycosylated-α-DG (g-α-DG) in muscles of both FKRP mutant animals and patients. METHODS: We examined the expression of g-α-DG in limb, diaphragm, and cardiac muscles of newborn FKRP mutants and LARGE(myd) mice with IIH6 antibody...
April 2017: Muscle & Nerve
https://www.readbyqxmd.com/read/27493216/carbohydrate-binding-domain-of-the-pomgnt1-stem-region-modulates-o-mannosylation-sites-of-%C3%AE-dystroglycan
#16
Naoyuki Kuwabara, Hiroshi Manya, Takeyuki Yamada, Hiroaki Tateno, Motoi Kanagawa, Kazuhiro Kobayashi, Keiko Akasaka-Manya, Yuriko Hirose, Mamoru Mizuno, Mitsunori Ikeguchi, Tatsushi Toda, Jun Hirabayashi, Toshiya Senda, Tamao Endo, Ryuichi Kato
The dystrophin glycoprotein complex, which connects the cell membrane to the basement membrane, is essential for a variety of biological events, including maintenance of muscle integrity. An O-mannose-type GalNAc-β1,3-GlcNAc-β1,4-(phosphate-6)-Man structure of α-dystroglycan (α-DG), a subunit of the complex that is anchored to the cell membrane, interacts directly with laminin in the basement membrane. Reduced glycosylation of α-DG is linked to some types of inherited muscular dystrophy; consistent with this relationship, many disease-related mutations have been detected in genes involved in O-mannosyl glycan synthesis...
August 16, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27439679/fkrp-mutations-including-a-founder-mutation-cause-phenotype-variability-in-chinese-patients-with-dystroglycanopathies
#17
Xiaona Fu, Haipo Yang, Cuijie Wei, Hui Jiao, Shuo Wang, Yanling Yang, Chunxi Han, Xiru Wu, Hui Xiong
Mutations in the fukutin-related protein (FKRP) gene have been associated with dystroglycanopathies, which are common in Europe but rare in Asia. Our study aimed to retrospectively analyze and characterize the clinical, myopathological and genetic features of 12 Chinese patients with FKRP mutations. Three patients were diagnosed with congenital muscular dystrophy type 1C (MDC1C) and nine patients were diagnosed with limb girdle muscular dystrophy type 2I (LGMD2I). Three muscle biopsy specimens had dystrophic changes and reduced glycosylated α-dystroglycan staining, and two showed reduced expression of laminin α2...
December 2016: Journal of Human Genetics
https://www.readbyqxmd.com/read/27257474/four-week-rapamycin-treatment-improves-muscular-dystrophy-in-a-fukutin-deficient-mouse-model-of-dystroglycanopathy
#18
Steven J Foltz, Junna Luan, Jarrod A Call, Ankit Patel, Kristen B Peissig, Marisa J Fortunato, Aaron M Beedle
BACKGROUND: Secondary dystroglycanopathies are a subset of muscular dystrophy caused by abnormal glycosylation of α-dystroglycan (αDG). Loss of αDG functional glycosylation prevents it from binding to laminin and other extracellular matrix receptors, causing muscular dystrophy. Mutations in a number of genes, including FKTN (fukutin), disrupt αDG glycosylation. METHODS: We analyzed conditional Fktn knockout (Fktn KO) muscle for levels of mTOR signaling pathway proteins by Western blot...
2016: Skeletal Muscle
https://www.readbyqxmd.com/read/27194101/ispd-produces-cdp-ribitol-used-by-fktn-and-fkrp-to-transfer-ribitol-phosphate-onto-%C3%AE-dystroglycan
#19
Isabelle Gerin, Benoît Ury, Isabelle Breloy, Céline Bouchet-Seraphin, Jennifer Bolsée, Mathias Halbout, Julie Graff, Didier Vertommen, Giulio G Muccioli, Nathalie Seta, Jean-Marie Cuisset, Ivana Dabaj, Susana Quijano-Roy, Ammi Grahn, Emile Van Schaftingen, Guido T Bommer
Mutations in genes required for the glycosylation of α-dystroglycan lead to muscle and brain diseases known as dystroglycanopathies. However, the precise structure and biogenesis of the assembled glycan are not completely understood. Here we report that three enzymes mutated in dystroglycanopathies can collaborate to attach ribitol phosphate onto α-dystroglycan. Specifically, we demonstrate that isoprenoid synthase domain-containing protein (ISPD) synthesizes CDP-ribitol, present in muscle, and that both recombinant fukutin (FKTN) and fukutin-related protein (FKRP) can transfer a ribitol phosphate group from CDP-ribitol to α-dystroglycan...
May 19, 2016: Nature Communications
https://www.readbyqxmd.com/read/27142102/robust-genotyping-tool-for-autosomal-recessive-type-of-limb-girdle-muscular-dystrophies
#20
Inna Inashkina, Eriks Jankevics, Janis Stavusis, Inta Vasiljeva, Kristine Viksne, Ieva Micule, Jurgis Strautmanis, Maruta S Naudina, Loreta Cimbalistiene, Vaidutis Kucinskas, Astrida Krumina, Algirdas Utkus, Birute Burnyte, Ausra Matuleviciene, Baiba Lace
BACKGROUND: Limb-girdle muscular dystrophies are characterized by predominant involvement of the shoulder and pelvic girdle and trunk muscle groups. Currently, there are 31 genes implicated in the different forms of limb-girdle muscular dystrophies, which exhibit similar phenotypes and clinical overlap; therefore, advanced molecular techniques are required to achieve differential diagnosis. METHODS: We investigated 26 patients from Latvia and 34 patients from Lithuania with clinical symptoms of limb-girdle muscular dystrophies, along with 565 healthy unrelated controls from general and ethnic populations using our developed test kit based on the Illumina VeraCode GoldenGate genotyping platform, Ion AmpliSeq Inherited Disease Panel and direct sequencing of mutations in calpain 3 (CAPN3), anoctamin 5 (ANO5) and fukutin related protein (FKRP) genes...
May 4, 2016: BMC Musculoskeletal Disorders
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