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FKRP gene
URL of this page: https://medlineplus.gov/genetics/gene/fkrp/

FKRP gene

fukutin related protein

Normal Function

The FKRP gene provides instructions for making a protein called fukutin-related protein (FKRP). This protein is present in many of the body's tissues but is particularly abundant in the brain, heart (cardiac) muscle, and muscles used for movement (skeletal muscles). Within cells, FKRP is found in a specialized structure called the Golgi apparatus, where newly produced proteins are modified.

FKRP is involved in a process called glycosylation. Through this chemical process, sugar molecules are added to certain proteins. In particular, FKRP adds a molecule called ribitol 5-phosphate to the chain of sugars attached to a protein called alpha (α)-dystroglycan. Glycosylation is critical for the normal function of α-dystroglycan.

The α-dystroglycan protein helps anchor the structural framework inside each cell (cytoskeleton) to the lattice of proteins and other molecules outside the cell (extracellular matrix). In skeletal muscles, glycosylated α-dystroglycan helps stabilize and protect muscle fibers. In the brain, it helps direct the movement (migration) of nerve cells (neurons) during early development.

Health Conditions Related to Genetic Changes

Walker-Warburg syndrome

At least five mutations in the FKRP gene have been found to cause Walker-Warburg syndrome. This condition is the most severe form of a group of disorders known as congenital muscular dystrophies. Walker-Warburg syndrome causes skeletal muscle weakness and abnormalities of the brain and eyes. Because of the severity of the problems caused by this condition, affected individuals usually do not survive past early childhood.

Many FKRP gene mutations involved in Walker-Warburg syndrome change single protein building blocks (amino acids) in FKRP. The altered protein cannot reach the Golgi apparatus and is instead broken down, reducing the amount of functional FKRP.

A shortage of FKRP prevents the normal glycosylation of α-dystroglycan. As a result, α-dystroglycan can no longer effectively anchor cells to the proteins and other molecules that surround them. Without functional α-dystroglycan to stabilize the muscle fibers, they become damaged as they repeatedly contract and relax with use. The damaged fibers weaken and die over time, which affects the development, structure, and function of skeletal muscles in people with Walker-Warburg syndrome.

Defective α-dystroglycan also affects the migration of neurons during the early development of the brain. Instead of stopping when they reach their intended destinations, some neurons migrate past the surface of the brain into the fluid-filled space that surrounds it. Researchers believe that this problem with neuronal migration causes a brain abnormality called cobblestone lissencephaly, in which the surface of the brain lacks the normal folds and grooves and instead appears bumpy and irregular. Less is known about the effects of FKRP gene mutations in other parts of the body.

More About This Health Condition

Limb-girdle muscular dystrophy

MedlinePlus Genetics provides information about Limb-girdle muscular dystrophy

More About This Health Condition

Other disorders

Mutations in the FKRP gene have been found in a small number of people with congenital muscular dystrophy type 1C (MDC1C), which causes muscle weakness, brain abnormalities, and intellectual disability but usually does not affect the eyes. Rarely, mutations in the FKRP gene are associated with muscle eye brain disease, which causes muscle weakness, eye problems, and intellectual disability. The signs and symptoms of muscle eye brain disease are less severe than those of Walker-Warburg syndrome (described above). It is unclear how mutations in the FKRP gene cause several different muscular dystrophies.

Other Names for This Gene

  • FKRP_HUMAN
  • LGMD2I
  • MDC1C
  • MDDGA5
  • MDDGB5
  • MDDGC5

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

  • Beltran-Valero de Bernabe D, Voit T, Longman C, Steinbrecher A, Straub V, Yuva Y, Herrmann R, Sperner J, Korenke C, Diesen C, Dobyns WB, Brunner HG, van Bokhoven H, Brockington M, Muntoni F. Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker-Warburg syndrome. J Med Genet. 2004 May;41(5):e61. doi: 10.1136/jmg.2003.013870. No abstract available. Citation on PubMed or Free article on PubMed Central
  • Boito CA, Melacini P, Vianello A, Prandini P, Gavassini BF, Bagattin A, Siciliano G, Angelini C, Pegoraro E. Clinical and molecular characterization of patients with limb-girdle muscular dystrophy type 2I. Arch Neurol. 2005 Dec;62(12):1894-9. doi: 10.1001/archneur.62.12.1894. Citation on PubMed
  • Esapa CT, Benson MA, Schroder JE, Martin-Rendon E, Brockington M, Brown SC, Muntoni F, Kroger S, Blake DJ. Functional requirements for fukutin-related protein in the Golgi apparatus. Hum Mol Genet. 2002 Dec 15;11(26):3319-31. doi: 10.1093/hmg/11.26.3319. Citation on PubMed
  • Esapa CT, McIlhinney RA, Blake DJ. Fukutin-related protein mutations that cause congenital muscular dystrophy result in ER-retention of the mutant protein in cultured cells. Hum Mol Genet. 2005 Jan 15;14(2):295-305. doi: 10.1093/hmg/ddi026. Epub 2004 Dec 1. Citation on PubMed
  • Gerin I, Ury B, Breloy I, Bouchet-Seraphin C, Bolsee J, Halbout M, Graff J, Vertommen D, Muccioli GG, Seta N, Cuisset JM, Dabaj I, Quijano-Roy S, Grahn A, Van Schaftingen E, Bommer GT. ISPD produces CDP-ribitol used by FKTN and FKRP to transfer ribitol phosphate onto alpha-dystroglycan. Nat Commun. 2016 May 19;7:11534. doi: 10.1038/ncomms11534. Citation on PubMed or Free article on PubMed Central
  • Kanagawa M, Kobayashi K, Tajiri M, Manya H, Kuga A, Yamaguchi Y, Akasaka-Manya K, Furukawa JI, Mizuno M, Kawakami H, Shinohara Y, Wada Y, Endo T, Toda T. Identification of a Post-translational Modification with Ribitol-Phosphate and Its Defect in Muscular Dystrophy. Cell Rep. 2016 Mar 8;14(9):2209-2223. doi: 10.1016/j.celrep.2016.02.017. Epub 2016 Feb 25. Citation on PubMed
  • Kava M, Chitayat D, Blaser S, Ray PN, Vajsar J. Eye and brain abnormalities in congenital muscular dystrophies caused by fukutin-related protein gene (FKRP) mutations. Pediatr Neurol. 2013 Nov;49(5):374-8. doi: 10.1016/j.pediatrneurol.2013.06.022. Citation on PubMed
  • Trovato R, Astrea G, Bartalena L, Ghirri P, Baldacci J, Giampietri M, Battini R, Santorelli FM, Fiorillo C. Elevated serum creatine kinase and small cerebellum prompt diagnosis of congenital muscular dystrophy due to FKRP mutations. J Child Neurol. 2014 Mar;29(3):394-8. doi: 10.1177/0883073812474951. Epub 2013 Feb 17. Citation on PubMed
  • Willer T, Inamori K, Venzke D, Harvey C, Morgensen G, Hara Y, Beltran Valero de Bernabe D, Yu L, Wright KM, Campbell KP. The glucuronyltransferase B4GAT1 is required for initiation of LARGE-mediated alpha-dystroglycan functional glycosylation. Elife. 2014 Oct 3;3:e03941. doi: 10.7554/eLife.03941. Citation on PubMed or Free article on PubMed Central

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