Fukutin-Related Protein: From Pathology to Treatments

• Published in: Trends in cell biology Vol. 31; no. 3; pp. 197 - 210
• Main Authors: Ortiz-Cordero, Carolina, Azzag, Karim, Perlingeiro, Rita C.R.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2021; Elsevier BV
• Subjects: Cell therapy; congenital muscular dystrophy; Cytoskeleton; Dystroglycan; dystroglycanopathy; Dystroglycans - genetics; Dystroglycans - metabolism; Dystrophy; Extracellular matrix; FCMD protein; Gene transfer; Glycosylation; Glycosyltransferase; Glycosyltransferases - metabolism; Humans; limb-girdle; Muscular Dystrophies - genetics; Muscular Dystrophies - therapy; Muscular dystrophy; Mutation; Pentosyltransferases - genetics; Pentosyltransferases - metabolism; Proteins; α-dystroglycan; limb-girdle; congenital muscular dystrophy; glycosylation; muscular dystrophy; α-dystroglycan; dystroglycanopathy
• ISSN: 0962-8924; 1879-3088
• DOI: 10.1016/j.tcb.2020.11.003

Fukutin-related protein (FKRP) is a glycosyltransferase involved in the functional glycosylation of α-dystroglycan (DG), a key component in the link between the cytoskeleton and the extracellular matrix (ECM). Mutations in FKRP lead to dystroglycanopathies with broad severity, including limb-girdle and congenital muscular dystrophy. Studies over the past 5 years have elucidated the function of FKRP, which has expanded the number of therapeutic opportunities for patients carrying FKRP mutations. These include small molecules, gene delivery, and cell therapy. Here we summarize recent findings on the function of FKRP and describe available models for studying diseases and testing therapeutics. Lastly, we highlight preclinical studies that hold potential for the treatment of FKRP-associated dystroglycanopathies. FKRP is a ribitol-5-phosphate transferase involved in α-DG glycosylation. Mutations in FKRP have been associated with a broad spectrum of dystroglycanopathies.Several FKRP mutant models have been generated to better understand disease pathogenesis of FKRP-associated dystroglycanopathies as well as to develop therapeutics.Several strategies, including the use of small molecules, gene therapy, and cell therapy, have shown improvement of disease phenotype as evidenced by rescue of α-DG functional glycosylation.