Fukutin-related protein (FKRP) (FKRP)

Fukutin-related protein (FKRP) is a Golgi-resident glycosyltransferase essential for the functional maturation of alpha-dystroglycan (α-DG), a key component of the dystrophin-glycoprotein complex that links the cytoskeleton to the extracellular matrix (UniProt: Q9H9S5). Specifically, FKRP functions as a ribitol-5-phosphate transferase, catalyzing the transfer of ribitol-5-phosphate from CDP-ribitol to the O-mannose-linked carbohydrate chain on α-DG (PubMed: 26923225). Mutations in the FKRP gene lead to a spectrum of autosomal recessive disorders known as dystroglycanopathies, ranging from the relatively mild limb-girdle muscular dystrophy R9 (formerly LGMD2I) to severe congenital muscular dystrophies like Walker-Warburg syndrome (NIH: Genetic and Rare Diseases Information Center). These conditions are characterized by progressive muscle weakness, cardiomyopathy, and in severe cases, central nervous system involvement. Therapeutic strategies currently under investigation include gene replacement therapy using adeno-associated virus (AAV) vectors to deliver a functional FKRP gene and substrate supplementation therapy with ribitol (BBP-418) to enhance the glycosylation pathway (ClinicalTrials.gov: NCT04800874, NCT05230472).

Other names

LGMD2IMDC1CMDDGA5MDDGB5MDDGC5Fukutin-related protein

Substrate supplementation (ribitol) to increase the pool of CDP-ribitol for glycosylation, or AAV-mediated gene replacement to restore functional FKRP protein expression (PubMed: 33009450, ClinicalTrials.gov: NCT04800874).