On this page
FKRP
fukutin related protein
The FKRP gene provides instructions for making fukutin-related protein, which is vital for glycosylation and the proper function of muscles and the brain. The FKRP gene codes for the fukutin-related protein (FKRP), crucial for modifying other proteins through a process called glycosylation.
FKRP is located on the long (q) arm of chromosome 19, at band 19q13.32. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 19 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The FKRP gene, or fukutin related protein, plays a critical role in cellular function, particularly in the brain, heart, and skeletal muscles. It provides instructions for producing the FKRP protein, which is found within a cellular organelle called the Golgi apparatus, responsible for modifying and packaging proteins. Understanding the FKRP gene is important for its association with a spectrum of inherited muscle and brain conditions.
Pathogenic variants in the FKRP gene are inherited in an autosomal recessive manner, meaning an individual must inherit two copies of the altered gene (one from each parent) to be affected by an associated condition. Carriers typically do not show symptoms but can pass the gene variant to their children.
What the gene does
The FKRP protein is fundamentally involved in a biochemical process known as glycosylation. This process entails the addition of sugar molecules to specific proteins, which is crucial for their proper structure and biological activity. Specifically, FKRP facilitates the addition of ribitol 5-phosphate to the sugar chain attached to alpha-dystroglycan [PMID:16121285].
Alpha-dystroglycan is a key protein that helps connect the internal structural framework of cells (cytoskeleton) to the external matrix of proteins and other molecules surrounding the cell. In skeletal muscles, properly glycosylated alpha-dystroglycan helps to stabilise and protect muscle fibres from damage. In the brain, its correct glycosylation is important for guiding the movement of nerve cells during early developmental stages. Impaired FKRP function due to gene variants can disrupt these essential processes, leading to muscle weakness and developmental abnormalities in the brain [PMID:15340801].
Video: Genetics 101
Chromosome location
The FKRP gene is located on chromosome 19, specifically at position 19q13.32. This precise genomic address helps in identifying the gene's location within the human genome and is crucial for genetic mapping and diagnostic purposes.
Protein structure
The FKRP protein consists of 495 amino acids. Its domain architecture includes a Zinc finger loop, which spans amino acids 289-318. This structural element may contribute to the protein's function in glycosylation or interaction with other cellular components.
Key variants
Variants within the FKRP gene can alter the fukutin-related protein, affecting its ability to properly glycosylate other proteins. These genetic changes can range from single nucleotide changes to larger deletions or insertions within the gene sequence. The clinical impact of FKRP variants depends on their specific nature and location, and how significantly they impair protein function.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1000G>T | p.Glu334Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Walker-Warburg congenital muscular dystrophy |
c.1020C>G | p.Tyr340Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive limb-girdle muscular dystrophy type 2I |
c.1077G>A | p.Trp359Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Walker-Warburg congenital muscular dystrophy |
c.1208dup | p.Arg404fs | Pathogenic/Likely pathogenic | ★★☆☆ | Walker-Warburg congenital muscular dystrophy |
c.1216C>T | p.Gln406Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 |
c.159_160delinsTT | p.Arg54Trp | Pathogenic | ★★☆☆ | Autosomal recessive limb-girdle muscular dystrophy |
c.217C>T | p.Gln73Ter | Pathogenic | ★★☆☆ | Walker-Warburg congenital muscular dystrophy |
c.265C>G | p.Pro89Ala | Pathogenic/Likely pathogenic | ★★☆☆ | Walker-Warburg congenital muscular dystrophy |
c.651_652dup | p.Val218fs | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.795_811del | p.Ala267fs | Pathogenic/Likely pathogenic | ★★☆☆ | Walker-Warburg congenital muscular dystrophy |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the FKRP gene are associated with a range of conditions, primarily congenital muscular dystrophies and limb-girdle muscular dystrophies. One of the most severe conditions linked to FKRP variants is Walker-Warburg syndrome, which causes significant muscle weakness, and abnormalities of the brain and eyes. Other related conditions include congenital muscular dystrophy type 1C (MDC1C), which may involve muscle weakness, intellectual disability, and occasionally brain abnormalities [PMID:15340801]. Limb-girdle muscular dystrophy is also associated with FKRP variants.
- Walker-Warburg syndrome Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic FKRP variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The FKRP gene is included in several NHS England Genomic Medicine Service national test panels. These panels cover conditions such as Acute rhabdomyolysis (R419), Arthrogryposis (R83), Congenital muscular dystrophy (R79), Foetal anomalies (R21), Hydrocephalus (R86), and Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies (R82). Its presence on these panels indicates its recognised clinical significance within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the FKRP gene?
The FKRP gene provides instructions for the fukutin-related protein, which is essential for glycosylation, a process where sugar molecules are added to other proteins. This is particularly important for the proper function of alpha-dystroglycan in muscle and brain development.
How are conditions associated with FKRP inherited?
Conditions linked to the FKRP gene are inherited in an autosomal recessive pattern. This means an individual must inherit two altered copies of the gene, one from each parent, to develop the condition.
What is Walker-Warburg syndrome?
Walker-Warburg syndrome is a severe congenital muscular dystrophy caused by variants in the FKRP gene. It is characterised by significant muscle weakness, and abnormalities affecting the brain and eyes.
References
- Kanagawa M, Kobayashi K, Tajiri M. Identification of a Post-translational Modification with Ribitol-Phosphate and Its Defect in Muscular Dystrophy. Cell reports. 2016. PMID: 26923585
- Gerin I, Ury B, Breloy I. ISPD produces CDP-ribitol used by FKTN and FKRP to transfer ribitol phosphate onto α-dystroglycan. Nature communications. 2016. PMID: 27194101
- Trovato R, Astrea G, Bartalena L. Elevated serum creatine kinase and small cerebellum prompt diagnosis of congenital muscular dystrophy due to FKRP mutations. Journal of child neurology. 2014. PMID: 23420653
- Willer T, Inamori K, Venzke D. The glucuronyltransferase B4GAT1 is required for initiation of LARGE-mediated α-dystroglycan functional glycosylation. eLife. 2014. PMID: 25279699
- Kava M, Chitayat D, Blaser S. Eye and brain abnormalities in congenital muscular dystrophies caused by fukutin-related protein gene (FKRP) mutations. Pediatric neurology. 2013. PMID: 24139536
- 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. Human molecular genetics. 2005. PMID: 15574464
- Boito CA, Melacini P, Vianello A. Clinical and molecular characterization of patients with limb-girdle muscular dystrophy type 2I. Archives of neurology. 2005. PMID: 16344347
- Beltran-Valero de Bernabé D, Voit T, Longman C. Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker-Warburg syndrome. Journal of medical genetics. 2004. PMID: 15121789
- Esapa CT, Benson MA, Schröder JE. Functional requirements for fukutin-related protein in the Golgi apparatus. Human molecular genetics. 2002. PMID: 12471058