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fukutin related protein

Ibrahim El-Battrawy, Zhihan Zhao, Huan Lan, Xin Li, Gökhan Yücel, Siegfried Lang, Katherine Sattler, Jan-Dierk Schünemann, Wolfram-Hubertus Zimmermann, Lukas Cyganek, Jochen Utikal, Thomas Wieland, Karen Bieback, Ralf Bauer, Antonius Ratte, Regina Pribe-Wolferts, Kleopatra Rapti, Daniel Nowak, Janina Wittig, Dierk Thomas, Patrick Most, Hugo A Katus, Ursula Ravens, Constanze Schmidt, Martin Borggrefe, Xiao-Bo Zhou, Oliver J Müller, Ibrahim Akin
BACKGROUND: Limb-Girdle muscular dystrophies (LGMD) are a heritable group of genetically determined disorders with a primary involvement of the pelvic or shoulder girdle musculature with partially cardiac manifestation, such as dilated cardiomyopathy (DCM) and life-threatening tachyarrhythmia. We report here that human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes from a patient with LGMD2I and DCM associated with recurrent ventricular tachycardia displayed ion channel dysfunction and abnormality of calcium homeostasis...
March 2018: Circ Genom Precis Med
Ryuta Nishihara, Kazuhiro Kobayashi, Reiko Imae, Hiroki Tsumoto, Hiroshi Manya, Mamoru Mizuno, Motoi Kanagawa, Tamao Endo, Tatsushi Toda
Dystroglycanopathies are a group of muscular dystrophies that are caused by abnormal glycosylation of dystroglycan; currently 18 causative genes are known. Functions of the dystroglycanopathy genes fukutin, fukutin-related protein (FKRP), and transmembrane protein 5 (TMEM5) were most recently identified; fukutin and FKRP are ribitol-phosphate transferases and TMEM5 is a ribitol xylosyltransferase. In this study, we show that fukutin, FKRP, and TMEM5 form a complex while maintaining each of their enzyme activities...
February 22, 2018: Biochemical and Biophysical Research Communications
Carmen Haro, Mary Luz Uribe, Cristina Quereda, Jesús Cruces, José Martín-Nieto
Purpose: Dystroglycanopathies are a heterogeneous group of recessive neuromuscular dystrophies that affect the muscle, brain and retina, and are caused by deficiencies in the O-glycosylation of α-dystroglycan. This post-translational modification is essential for the formation and maintenance of ribbon synapses in the retina. Fukutin and fukutin-related protein (FKRP) are two glycosyltransferases whose deficiency is associated with severe dystroglycanopathies. These enzymes carry out in vitro the addition of a tandem ribitol 5-phosphate moiety to the so-called core M3 phosphotrisaccharide of α-dystroglycan...
2018: Molecular Vision
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...
2017: Journal of Neuromuscular Diseases
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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