fukutin related protein

The diaphragm muscle is essential for breathing, and its dysfunctions can be fatal. Many disorders affect the diaphragm, including muscular dystrophies. Despite the clinical relevance of targeting the diaphragm, there have been few studies evaluating diaphragm function following a given experimental treatment, with most of these involving anti-inflammatory drugs or gene therapy. Cell-based therapeutic approaches have shown success promoting muscle regeneration in several mouse models of muscular dystrophy, but these have focused mainly on limb muscles...

Dystroglycanopathies are a group of muscle degenerative diseases characterized with significant reduction in matriglycan expression critical in disease pathogenesis. Missense point mutations in the Fukutin-related protein (FKRP) gene cause variable reduction in the synthesis of matriglycan on alpha-dystroglycan (α-DG) and a wide range of disease severity. Data analyses of muscle biopsies from patients fail to show consistent correlation between the levels of matriglycan and clinical phenotypes. By reviewing clinical reports in conjunction with analysis of clinically relevant mouse models, we identify likely causes for the confusion...

The core M3 O-mannosyl glycan on α-dystroglycan serves as the binding epitope for extracellular matrix molecules. Defects in core M3 glycans cause congenital muscular dystrophies that are collectively known as dystroglycanopathies. The core M3 glycan contains a tandem D-ribitol-5-phosphate (Rbo5P) structure, which is synthesized by the Rbo5P-transferases fukutin (FKTN) and fukutin-related protein (FKRP) using CDP-ribitol (CDP-Rbo) as a donor substrate. CDP-Rbo is synthesized from CTP and Rbo5P by CDP-Rbo pyrophosphorylase A (CRPPA)...

BACKGROUND: Limb-girdle muscular dystrophy R9 (LGMDR9) is a chronic progressive hereditary muscle disease, related to the Fukutin Related Protein (FKRP) gene, that may cause major disabilities, cardiomyopathy, and ventilatory failure. Knowledge of how LGMDR9 affects health-related quality of life (HRQoL) is relevant in treatment and care. OBJECTIVE: To investigate HRQoL in the Norwegian LGMDR9 population over 14 months and relation to fatigue and sleep quality. METHODS: Participants (16+ years) of the Norwegian LGMDR9 cohort study completed two HRQoL measures, i...

Limb-Girdle Muscular Dystrophy R9 (LGMDR9) is a dystroglycanopathy caused by Fukutin-related protein (FKRP) defects leading to the deficiency of α-DG glycosylation, essential to membrane integrity. Recombinant adeno-associated viral vector (rAAV) gene therapy offers great therapeutic promise for such neuromuscular disorders. Pre-clinical studies have paved the way for a phase 1/2 clinical trial aiming to evaluate the safety and efficacy of FKRP gene therapy in LGMDR9 patients. To demonstrate product activity, quality, and consistency throughout product and clinical development, regulatory authorities request several quality controls, including a potency assay aiming to demonstrate and quantify the intended biological effect of the gene therapy product...

Limb-girdle muscular dystrophy type R9 (LGMDR9) is a muscle-wasting disease that begins in the hip and shoulder regions of the body. This disease is caused by mutations in fukutin-related protein (FKRP), a glycosyltransferase critical for maintaining muscle cell integrity. Here we investigated potential gene therapies for LGMDR9 containing an FKRP expression construct with untranslated region (UTR) modifications. Initial studies treated an aged dystrophic mouse model (FKRPP448L ) with adeno-associated virus vector serotype 6 (AAV6)...

Pain is prevalent in individuals with limb-girdle muscular dystrophy (LGMD) R9, but impact on daily living and correlation with fatigue remain unknown. Patient-Reported Outcomes Measurement Information System (PROMIS) pain interference and fatigue short forms were completed annually by 23 children and 54 adults with biallelic fukutin-related protein (FKRP) variants for up to six years. Concurrent motor and pulmonary function were evaluated. Pain interference T-scores were near the normal mean of 50 by linear mixed model analysis (48...

BACKGROUND: The phenotypic spectrum of Fukutin-related protein (FKRP) mutations is highly variable and comprises of limb girdle muscular dystrophy (LGMD) R9 (previously LGMD 2I) and FKRP related congenital muscular dystrophies. OBJECTIVE: To identify the distinct genotype phenotype pattern in Indian patients with FKRP gene mutations. METHODS: We retrospectively reviewed the case files of patients with muscular dystrophy having a genetically confirmed FKRP mutation...

Dystroglycan (DG), a muscular transmembrane protein, plays a critical role in transducing extracellular matrix-derived signals to the cytoskeleton and provides physical strength to skeletal muscle cell membranes. The extracellular domain of DG, α-DG, displays unique glycosylation patterns. Fully functional glycosylation is required for this domain to interact with components of extracellular matrices, including laminin. One of the unique sugar compositions found in such functional glycans on DG is two ribitol phosphates (RboP) that are transferred by the sequential actions of fukutin (FKTN) and fukutin-related protein (FKRP), which use CDP-ribitol as a donor substrate...

We aimed to investigate the epidemiology and natural history of FKRP-related limb-girdle muscular dystrophy R9 (LGMDR9) in Norway. We identified 153 genetically confirmed subjects making the overall prevalence 2.84/100,000, the highest reported figure worldwide. Of the 153 subjects, 134 (88 %) were homozygous for FKRP c.826C>A giving a carrier frequency for this variant of 1/101 in Norway. Clinical questionnaires and patient notes from 101 subjects, including 88 c.826C>A homozygotes, were reviewed, and 43/101 subjects examined clinically...

Limb Girdle Muscular Dystrophy 2I (LGMDR9) is one of the most common LGMD characterized by defects in glycosylation of α-dystroglycan (matriglycan) resulting from mutations of Fukutin-related protein (FKRP). There is no effective therapy currently available. We recently demonstrated that ribitol supplement increases levels of matriglycan in cells in vitro and in FKRP-P448L (P448L) mutant mouse model through drinking water administration. To be clinically relevant, we have now conducted a dose-escalating efficacy study by gavage in P448L mutant mice...

Ribitol phosphate modifications to the core M3 O -mannosyl glycan are important for the functional maturation of α-dystroglycan. Three sequentially extended partial structures of the core M3 O -mannosyl glycan including a tandem ribitol phosphate were regio- and stereo-selectively synthesized: Rbo5P-3GalNAcβ, Rbo5P-1Rbo5P-3GalNAcβ, and Xylβ1-4Rbo5P-1Rbo5P-3GalNAcβ (Rbo5P, d-ribitol-5-phosphate; GalNAc, N -acetyl-d-galactosamine; Xyl, d-xylose). Rbo5P-3GalNAcβ with p -nitrophenyl at the aglycon part served as a substrate for ribitol phosphate transferase (FKRP, fukutin-related protein), and its product was glycosylated by the actions of a series of glycosyltransferases, namely, ribitol xylosyltransferase 1 (RXYLT1), β1,4-glucuronyltransferase 1 (B4GAT1), and like-acetyl-glucosaminyltransferase (LARGE)...

Limb-girdle muscular dystrophy R9 (LGMD2I, LGMDR9) is an autosomal recessive disorder caused by pathogenic variants in the fukutin-related protein ( FKRP ) gene. We describe a 17 year old boy with LGMDR9 whose symptoms began at age 5 years. Muscle histopathology, immunostaining, and western blotting were consistent with a dystroglycanopathy. Genetic testing identified maternal inheritance of the most common pathogenic FKRP variant c.826C>A (p.L276I). Also detected was a novel insertion and duplication on the paternally inherited FKRP allele: a single nucleotide insertion (c...

The dystrophin-glycoprotein complex (DGC) links the intracellular cytoskeleton to the extracellular basement membrane, thereby providing structural support for the sarcolemma. Many patients with muscular dystrophies, particularly those with defects in cardiomyopathies with chamber dilation and myocardial dysfunction. Heart failure is the major cause of death for muscular dystrophy patients; however, the molecular pathomechanism remains unknown. Here, I show the detailed molecular pathogenesis of muscular dystrophy-associated cardiomyopathy in mice lacking the fukutin gene (Fktn), the causative gene for Fukuyama muscular dystrophy...

Fukutin-related protein (FKRP) is a glycosyltransferase involved in glycosylation of alpha-dystroglycan (α-DG). Mutations in FKRP are associated with muscular dystrophies (MD) ranging from limb-girdle LGMDR9 to Walker-Warburg Syndrome (WWS), a severe type of congenital MD. Although hypoglycosylation of α-DG is the main hallmark of this group of diseases, a full understanding of the underlying pathophysiology is still missing. Here, we investigated molecular mechanisms impaired by FKRP mutations in pluripotent stem (PS) cell-derived myotubes...

α-Dystroglycan (α-DG) is a glycoprotein specifically modified with O-mannosyl glycans bearing long polysaccharides, termed matriglycans, which comprise repeating units of glucuronic acid and xylose. The matriglycan is linked to the O-mannosyl glycan core through two ribitol phosphate units that can be replaced with glycerol phosphate (GroP) units synthesized by fukutin and fukutin-related protein that transfer GroP from CDP-Gro. Here, we found that forced expression of the bacterial CDP-Gro synthase, TagD, from Bacillus subtilis could result in the overproduction of CDP-Gro in human colon carcinoma HCT116 cells...

Mutation in the fukutin-related protein (FKRP) gene causes alpha-dystroglycanopathies, a group of autosomal recessive disorders associated with defective glycosylated alpha-dystroglycan (α-DG). The disease phenotype shows a broad spectrum, from the most severe congenital form involving brain and eye anomalies to milder limb-girdle form. FKRP-related alpha-dystroglycanopathies are common in European countries. However, a limited number of patients have been reported in Asian countries. Here, we presented the clinical, pathological, and genetic findings of nine patients with FKRP mutations identified at a single muscle repository center in Japan...

Mutations in the fukutin-related protein (FKRP) gene result in a broad spectrum of muscular dystrophy (MD) phenotypes, including the severe Walker-Warburg syndrome (WWS). Here, we develop a gene-editing approach that replaces the entire mutant open reading frame with the wild-type sequence to universally correct all FKRP mutations. We apply this approach to correct FKRP mutations in induced pluripotent stem (iPS) cells derived from patients displaying broad clinical severity. Our findings show rescue of functional α-dystroglycan (α-DG) glycosylation in gene-edited WWS iPS cell-derived myotubes...

α-Dystroglycan (α-DG) is a highly glycosylated cell-surface protein. Defective O-mannosyl glycan on α-DG is associated with muscular dystrophies and cancer. In the biosynthetic pathway of the O-mannosyl glycan, fukutin (FKTN) and fukutin-related protein (FKRP) transfer ribitol phosphate (RboP). Previously, we reported that FKTN and FKRP can also transfer glycerol phosphate (GroP) from CDP-glycerol (CDP-Gro) and showed the inhibitory effects of CDP-Gro on functional glycan synthesis by preventing glycan elongation in vitro...

This review recollects my initial research focus on revertant fibers (expressing dystrophin in the background of frame-shifting mutation) in Duchenne muscular dystrophy (DMD) muscles in Professor Terrence Partridge's Muscle Cell Biology Laboratory in MRC Clinical Research Science Center, Harmmersmith Hospital, London, UK. Our data indicated that revertant fibers are most likely resulted from epigenetic random events which skip exon(s) flanking the mutated exon, leading to the restoration of the reading frame...