Quantitative Measurement of Glycosylated ⍺-Dystroglycan as a Biomarker for Disease Severity in Limb-Girdle Muscular Dystrophy Type 2I/R9
Year: 2026
Type: article
Study design: Observational Study
Abstract: Background and Objectives: Limb-girdle muscular dystrophy type 2I (LGMD2I/R9) is caused by biallelic variants in the gene for Fukutin-related protein (FKRP), an enzyme required for proper glycosylation of α-dystroglycan (⍺DG), a critical structural protein of the dystrophin glycoprotein complex. Hypoglycosylation of αDG results in impaired function of αDG, which in turn leads to chronic myocyte injury and muscular dystrophy. The "Biomarker Development in LGMD2I/R9" (MLB-01-001) natural history study explored glycosylated ⍺DG as a muscle biomarker for LGMD2I/R9 to support clinical trial design for the development of potential therapeutics. Methods: MLB-01-001 was a prospective, 12-month observational study of clinically affected participants 10-65 years of age with genetically confirmed LGMD2I/R9 at 11 academic centers in the United States and Denmark. Tibialis anterior (TA) muscle biopsies were obtained at baseline, month 6, month 9, and/or month 12 and measured for glycosylated ⍺DG levels relative to that of an unaffected human control using a validated, quantitative western blot assay. Results: genotypes (4.6% of control, IQR 4.3%, n = 17). Glycosylated αDG levels remained stable over 6-12 months. Discussion: Glycosylated ⍺DG was consistently lower in participants with LGMD2I/R9 than in the unaffected control, reflected disease severity by genotype, and remained stable over 6-12 months, suggesting that it may be an appropriate biomarker for assessing the effect of potential therapies for LGMD2I/R9. Trial Registration Information: ClinicalTrials.gov ID NCT04202627, first posted 17 Dec 2019.
Source: Neurology Genetics
Authors: John Vissing, Tahseen Mozaffar, Nicholas E. Johnson, Katherine D. Mathews, Matthew P. Wicklund, Conrad Weihl, Doris G. Leung, Jeffrey M. Statland, Peter B. Kang, Carla D. Zingariello, Linda Pax Lowes, Urvi Desai, Kameron Bates, Lindsay N. Alfano, Han Xie, Jessica St Romain, Tricia Blankenbiller, George McLendon, Thulashitha Rajasingham, Marjet Heitzer, Alyssa X. Wu-Zhang, Kenneth Tripp, Hector M. Rodriguez, Douglas Sproule
Institutions: University of Copenhagen, Rigshospitalet, University of California, Irvine, Virginia Commonwealth University, University of Iowa, University of Iowa Hospitals and Clinics, The University of Texas at San Antonio Health Science Center, Washington University in St. Louis, Kennedy Krieger Institute, University of Kansas Medical Center, University of Minnesota, University of Florida, Nationwide Children's Hospital, Abigail Wexner Research Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,300
Funders: ALS Association, Friedreich's Ataxia Research Alliance, AstraZeneca, Sanofi, Muscular Dystrophy Association, Biogen, Alexion Pharmaceuticals, Alnylam Pharmaceuticals, Cumberland Pharmaceuticals, Virginia Commonwealth University, Regeneron Pharmaceuticals, Vertex Pharmaceuticals, Friends of FSH Research, AveXis, Sarepta Therapeutics, Amicus Therapeutics, Harmony Biosciences, Argenx, Horizon Therapeutics, Italfarmaco, National Institutes of Health, Centers for Disease Control and Prevention, Sanofi Genzyme, Spark Therapeutics, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Advancing Translational Sciences
OpenAlex ID: W7147288703