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.[1] Fukutin is expressed in the mammalian retina and is located in the Golgi complex of retinal neurons.[2]

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.[3] 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.[4] 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.[5] 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.[6]

See also

References

  1. ^ "FKRP gene: MedlinePlus Genetics". medlineplus.gov. Retrieved 2022-05-05.
  2. ^ Haro C, Uribe ML, Quereda C, Cruces J, Martín-Nieto J (2018). "Expression in retinal neurons of fukutin and FKRP, the protein products of two dystroglycanopathy-causative genes". Molecular Vision. 24: 43–58. PMC 5783743. PMID 29416295
  3. ^ Ortiz-Cordero C, Azzag K, Perlingeiro RC (March 2021). "Fukutin-Related Protein: From Pathology to Treatments". Trends in Cell Biology. 31 (3): 197–210. doi:10.1016/j.tcb.2020.11.003. PMC 8657196. PMID 33272829
  4. ^ "FKRP gene: MedlinePlus Genetics". medlineplus.gov. Retrieved 2022-05-05.
  5. ^ Mercuri E, Topaloglu H, Brockington M, Berardinelli A, Pichiecchio A, Santorelli F, Rutherford M, Talim B, Ricci E, Voit T, Muntoni F (February 2006). "Spectrum of brain changes in patients with congenital muscular dystrophy and FKRP gene mutations". Archives of Neurology. 63 (2): 251–257. doi:10.1001/archneur.63.2.251. hdl:11655/15735. PMID 16476814
  6. ^ Ma K, Huang S, Ng KK, Lake NJ, Joseph S, Xu J, Lek A, Ge L, Woodman KG, Koczwara KE, Cohen J, Ho V, O'Connor CL, Brindley MA, Campbell KP, Lek M (November 2024). "Saturation mutagenesis-reinforced functional assays for disease-related genes". Cell. 187 (23): 6707–6724.e22. doi:10.1016/j.cell.2024.08.047. PMC 11568926. PMID 39326416