Fukutin-related protein

Fukutin-related protein (FKRP) is also known as FKRP_HUMAN, LGMD2I, MDC1C, MDDGA5, MDDGB5, and MDDGC5. FKRP can be located in the brain, cardiac muscle and skeletal muscle, and in cells it is found in the Golgi apparatus.^[5] Fukutin is expressed in the mammalian retina and is located in the Golgi complex of retinal neurons.^[6]

The genomic location of the FKRP gene is on chromosome 19. FKRP is a ribitol-5-phosphate (enzyme) glycosyltransferase, which means this enzyme helps create glycosidic linkages to an acceptor. In glycosylation of α-dystroglycan (sugar chain) it adds a ribitol-5-phosphate onto the M3 core O-mannosylation of α-dystroglycan to create O-linked mannosylation.^[7] Without this linkage α-dystroglycan will not function properly, this can cause issues with the cytoskeleton, and extracellular matrix. In skeletal muscles the α-dystroglycan helps stabilize and protect muscle fibers, in the brain it directs movement of nerve cells.^[8] This could be caused by mutations that binds ribitol-5-phosphate to the α-dystroglycan incorrectly. These mutations have been found to be associated with congenital muscular dystrophy, dystroglycanopathies, and Walker-Warburg syndrome.^[9] The severity of these diseases are correlated to the amount of mutations occurring. Possible therapy options for FKRP mutations include small molecules, gene delivery, and cell therapy.

In 2024, a deep mutational scanning was conducted, which generated functional scores for all possible single nucleotide variants of the FKRP coding sequence.^[10]