Fukutin

Last updated

FKTN
Identifiers
Aliases FKTN , CMD1X, FCMD, LGMD2M, MDDGA4, MDDGB4, MDDGC4, fukutin, LGMDR13
External IDs OMIM: 607440; MGI: 2179507; HomoloGene: 31402; GeneCards: FKTN; OMA:FKTN - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2218

246179

Ensembl

ENSG00000106692

ENSMUSG00000028414

UniProt

O75072

Q8R507

RefSeq (mRNA)

NM_139309
NM_001363126
NM_001363127
NM_001363128

RefSeq (protein)

NP_647470
NP_001350055
NP_001350056
NP_001350057

Location (UCSC) Chr 9: 105.56 – 105.65 Mb Chr 4: 53.71 – 53.78 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Golgi apparatus where Fukutin proteins function and inhabit Human leukocyte, showing golgi - TEM.jpg
Golgi apparatus where Fukutin proteins function and inhabit

Fukutin is a protein that in humans is encoded by the FKTN gene. It is necessary for the maintenance of muscle integrity, cortical histogenesis, and normal ocular development. In humans this protein is encoded by the FCMD gene (also named FKTN), located on chromosome 9q31. [5] [6] The FKTN gene encodes a type II transmembrane protein that is central to the Golgi apparatus through an N- terminal signal anchor. [7] Fukutin is a crucial enzyme involved in modifying proteins, particularly alpha- dystroglycan, which links the cell's internal structure to the outside matrix, vital for muscle and brain health. It is suggested that Fukutin may be located in the extracellular matrix, where it interacts with a large complex encompassing both the inside and outside of muscle membranes. [7]

Discovery

Fuktuin (encoded by the FKTN gene) was discovered by two Japanese researchers, Kazuhiro Kobayashi and Tatsushi Toda, who liked the FKTN gene to Fukuyama congenital muscular dystrophy in 1998. [7] The protein was identified through positional cloning to find the gene responsible for Fukuyama congenital muscular dystrophy, a severe muscle disorder common in Japan. Researchers found the gene after linking it to chromosome 9q13, realizing mutations in FKTN caused the disease, leading to hypoglycosylation of alpha- dystroglycan and resulting in muscle weakness, brain defects and eye problems. They found that the FKTN gene provides instructions for Fukutin, a 461 amino acid protein. The discovery of Fukutin marked a major step forward in science towards understanding dystroglycanopathies. [7] [8]

In 2000, Atsuo Sasaki used Northern blot and RT-PCR analysis to determine that the fukutin gene is expressed at similar levels in both the fetal and mature brain, however, it is found to be dramatically reduced in brains with Fukuyama congenital muscular dystrophy (FCMD). In the FCMD brain, neurons in areas with no dysplasia show moderate expression while transcripts were undetectable in the over-migrated dysplastic region. The authors hypothesized that fukutin may influence neuronal migration itself rather than formation of the basement membrane. [7]

Later on in 2004 and 2005, researchers Hiroki Kurahashi and Takeshi Chiyonobu published their work on the Fukutin gene and its role in muscular dystrophy. They are co- authors on research papers that investigate the physiological function and pathological roles of Fukutin. Kurahashi and Chiyonobu conducted research involving mice to understand the function of Fukutin, their work established crucial mouse models for the study of dystroglycanpathies. Early research demonstrated that complete Fukutin knockout in mice resulted in embryonic lethality, primarily due to fragile basement membranes. Analysis of fukutin- deficient chimeric mice revealed that defects in the basal lamina, caused by the loss of normal alpha- dystroglycan glycosylation, are key to brain malformations as seen in Fukuyama- type congenital muscular dystrophy. This concludes that fukutin is necessary for the maintenance of muscle strength, cortical histogenesis, and normal ocular development, and suggests linkage in function between fukutin and alpha- dystroglycan. [7] [9] [10]

Subcellular distribution

Fukutin is distributed to Golgi apparatus, the cell;s protein modification factory, adding sugars to other proteins. [11]

Function

Although its function is mostly unknown, Fukutin is a putative transmembrane protein that is ubiquitously expressed, although at higher levels in skeletal muscle, heart and brain. [12] It is localized to the cis-Golgi compartment, where it may be involved in the glycosylation of α-dystroglycan in skeletal muscle. During glycosylation, fukutin adds sugar molecules, specifically ribitol phosphate to alpha-dystroglycan. [13] This process may help anchor the cell's cytoskeleton to the extracellular matrix, stabilizing muscle fibers and preventing muscle corruption. [7]

The encoded protein is thought to be a glycosyltransferase and could play a role in brain development. [6] Fukutin is also vital for normal cortical development and neuronal functions, with expression in neurons and glial cells. Taken together, fukutin and α-DG are closely related in mature and immature human nerve cells in vivo, such as skeletal muscles and astrocytes. Fukutin may participate in basement membrane formation, synaptic function and neuronal migration in response to the glycosylation of α-DG. This may infer that fukutin may hold other functions relating to cellular differentiation. [14] Fukutin is expressed in the mammalian retina and is located in the Golgi complex of retinal neurons. [15] Fukutin may also play a role in cell proliferation and survival and gene transcription by enhancing cyclin D1 expression by forming a complex with AP-1 where Fukutin may serve as a potential co- factor for AP-1 as well. [16]

Research indicates fukutin might play a role in the presynaptic terminal of gamma-aminobutyric acid neurotransmitters (GABAergic). [17] Fukutin works with glutamate decarboxylase (GAD), an enzyme that synthesizes the neurotransmitter of gamma- aminobutyric acid and synaptophysin. A loss of fukutin appears to increase glutamate decarboxylase  expression, suggesting its involvement in regulating neurotransmitter release. These functions are considered unexpected  properties of fukutin, distinct from its primary role in protein glycosylation. [18]

Structure

Fukutin features a primary sequence of 461 amino acids that fold into secondary (alpha helices/ beta- sheets) and a specific 3D tertiary structure, often forming tetramers (quaternary structure) with other proteins. Fukutins also feature transmembrane regions and a catalytic domain important for adding sugar chains, such as Ribitol, to proteins such as alpha- dystroglycan. [19] [20] The secondary structure of alpha helices and beta sheets provides stability to the protein while a complex 3D shape in the tertiary structure allows it to function, potentially with stable metal ion (Mg2+) binding sites. Regarding domains of Fukutin, the protein is predicted to have a transmembrane region, a stem region, and a catalytic domain, similar to other glycosyltransferases. Fukutin has a predicted molecular mass of 53.7 kDa. [20]

Fukutin's transmembrane domain is a stable helix which is not affected by the width of the local membrane. Instead, this protein responds to changes in bilayer thickness using its ample mobility and ability to tilt within the bilayer. As the fukutin helix tilts, it is considered to be a function of bilayer thicken and shows implications for how the protein may respond to a variety of bilayer compositions found within the different intracellular compartments. This habit may suggest implications for protein packing and the formation of higher oligomeric structures, including the helix's preference for proteins to associate themselves with lipid bilayers with distinct physical properties. [21] [22]

Clinical significance

Defects in this gene are a cause of Fukuyama congenital muscular dystrophy, Walker-Warburg syndrome, limb-girdle muscular dystrophy type 2M (LGMD2M), and dilated cardiomyopathy type 1X (CMD1X). [6] [23] Fukutin and Fukutin- Related Protein are closely related glycosyltransferases who both work together to develop Fukutin gene therapies that aim to treat muscular dystrophies, including Limb- Girdle Muscular Dystrophy Type 2I/R9 (LGMD2I/R9), Walker-Warburg Syndrome and Fukuyama congenital muscular dystrophy. [24] [25]

Fukutin gene therapy uses viral vectors, mainly adenoids- associated viruses, to deliver healthy copy of the fukutin gene into patients with muscular dystrophies caused by Fukutin Related Protein (FKRP) mutations, aiming to restore proper alpha- dystroglycan glycosylation, showing promise in improving strength, reducing muscle damage, and lower CK levels. [26] While still being researched, Fukutin may also act as a tumor suppressor, inhibiting cell proliferation in cancers like astrocytoma and uterine cervical cancer. Fukutin may accomplish this by interacting with transcription factors such as AP-1 to regulate cell cycle genes. Fukutin cell suppression refers to its role in suppressing uncontrolled cell growth by slowing cell division, a function distinct from its primary glycosylation role. Fukutin binds to the promoter of the cell cycle gene, Cyclin D1, reducing its expression which slows cell cycle progression. [16] Suppressing fukutin increases cell proliferation, making it a potential target for cancer therapy. [27] [28]

Researchers are also investigating RNA interference (RNAi) to correct genetic defects in the fukutin (FKTN) gene, using experimental techniques such as exon skipping by antisense oligonucleotides (ASOs) delivered via AAV vectors to silence faulty gene messages and restore protein function. By correcting the mistake in the fukutin gene that blocks the chemical glycosylation of a biologically important protein, the cell can produce functional fukutin protein, restoring normal biochemical processes, researchers showed in patient- derived cell. [29]

Neurodegeneration

Fukutin is believed to be involved in the phosphorylation of tau protein. It is suggested that Fukutin, tau proteins, and glycogen synthase kinase- 3β (GSK-3β), form a complex. Suppression of fukutin leads to increased phosphorylation of both tau and glycogen synthase kinase-3β, while over- expression reduces it. This suggests that fukutin typically helps suppress tau phosphorylation, its absence or malfunction may contribute to the accumulation of abnormal hyperphosphorylated tau, which forms neurofibrillary tangles. [17] [18]

Other disorders

A lack of functional fukutin protein caused by genetic mutations in the fukutin gene may lead to a spectrum of conditions called FKTN- related disorders or also known as dystroglycanopathies. [11] These are severe, muscular dystrophies that often affect the muscles, brain and eyes. Mutations in the fukutin gene have been shown to result in Fukuyama congenital muscular dystrophy characterized by brain malformation which is one of the most common autosomal-recessive disorders in Japan. [30] The range of these conditions can vary from the mildest form, Limb- girdle muscular dystrophy type 2M (LGMD2M), to the most severe, Walker-Warburg syndrome. [11] [31]

A deficiency in the Fukutin enzyme results in defective α- dystroglycan, leading to a multitude of consequences. The body's muscle fibers become weak and damaged during activity and begins to degenerate over time, leading to total muscle weakness. [32] [33] Defective α- dystroglycan affects the migration of neurons in the body's brain during early development which can cause structural defects like a bumpy, irregular brain surface, formally known as "cobblestone lissencephaly" or "polymicrogyria". This development can eventually lead to intellectual disabilities, developmental delays and seizures [11] Absence of Fukutin can also leave an individual's vision impaired, such as small eyes, cataracts, and tractional retinal detachment. [34] Lack of fukutin can also cause an individual to develop heart and respiratory issues. Progressive heart conditions, cardiomyopathy, and respiratory muscle weakness, which can lead to frequent lung infections, are common in more severe and advanced cases and can often cause a shortened life span. [23]

See also

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000106692 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000028414 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Toda T, Segawa M, Nomura Y, Nonaka I, Masuda K, Ishihara T, et al. (November 1993). "Localization of a gene for Fukuyama type congenital muscular dystrophy to chromosome 9q31-33". Nature Genetics. 5 (3): 283–286. doi:10.1038/ng1193-283. PMID   8275093.
  6. 1 2 3 "FKTN fukutin [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2025-12-18.
  7. 1 2 3 4 5 6 7 "Entry - *607440 - FUKUTIN; FKTN - OMIM - (OMIM.ORG)". omim.org. Retrieved 2025-12-18.
  8. ↑ Toda T, Kobayashi K, Kondo-Iida E, Sasaki J, Nakamura Y (March 2000). "The Fukuyama congenital muscular dystrophy story". Neuromuscular Disorders. 10 (3): 153–159. doi:10.1016/s0960-8966(99)00109-1. PMID   10734260.
  9. ↑ Beedle AM, Turner AJ, Saito Y, Lueck JD, Foltz SJ, Fortunato MJ, et al. (September 2012). "Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy". The Journal of Clinical Investigation. 122 (9): 3330–3342. doi:10.1172/JCI63004. PMC   3428090 . PMID   22922256.
  10. ↑ Chan YM, Keramaris-Vrantsis E, Lidov HG, Norton JH, Zinchenko N, Gruber HE, et al. (October 2010). "Fukutin-related protein is essential for mouse muscle, brain and eye development and mutation recapitulates the wide clinical spectrums of dystroglycanopathies". Human Molecular Genetics. 19 (20): 3995–4006. doi:10.1093/hmg/ddq314. PMID   20675713.
  11. 1 2 3 4 "FKTN gene: MedlinePlus Genetics". medlineplus.gov. Retrieved 2025-12-19.
  12. ↑ Hayashi YK, Ogawa M, Tagawa K, Noguchi S, Ishihara T, Nonaka I, et al. (July 2001). "Selective deficiency of alpha-dystroglycan in Fukuyama-type congenital muscular dystrophy". Neurology. 57 (1): 115–121. doi:10.1212/wnl.57.1.115. PMID   11445638.
  13. ↑ Kanagawa M, Toda T (2017). "Muscular Dystrophy with Ribitol-Phosphate Deficiency: A Novel Post-Translational Mechanism in Dystroglycanopathy". Journal of Neuromuscular Diseases. 4 (4): 259–267. doi:10.3233/JND-170255. PMC   5701763 . PMID   29081423.
  14. ↑ Hiroi A, Yamamoto T, Shibata N, Osawa M, Kobayashi M (April 2011). "Roles of fukutin, the gene responsible for fukuyama-type congenital muscular dystrophy, in neurons: possible involvement in synaptic function and neuronal migration". Acta Histochemica et Cytochemica. 44 (2): 91–101. doi:10.1267/ahc.10045. PMC   3096086 . PMID   21614170.
  15. ↑ 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.
  16. 1 2 Okamura Y, Yamamoto T, Tsukui R, Kato Y, Shibata N (November 2021). "Fukutin Protein Participates in Cell Proliferation by Enhancing Cyclin D1 Expression through Binding to the Transcription Factor Activator Protein-1: An In Vitro Study". International Journal of Molecular Sciences. 22 (22) 12153. doi: 10.3390/ijms222212153 . PMC   8622492 . PMID   34830034.
  17. 1 2 Yamamoto T, Okamura Y, Tsukui R, Kato Y, Onizuka H, Masui K (2022-10-17), "Perspective Chapter: Multiple Functions of Fukutin, the Gene Responsible for Fukuyama Congenital Muscular Dystrophy, Especially in the Central Nervous System", Potential Therapeutic Strategies for Muscular Dystrophy, IntechOpen, ISBN   978-1-83768-156-3 , retrieved 2025-12-19
  18. 1 2 Tsukui R, Yamamoto T, Okamura Y, Kato Y, Shibata N (February 2022). "Fukutin regulates tau phosphorylation and synaptic function: Novel properties of fukutin in neurons". Neuropathology. 42 (1): 28–39. doi:10.1111/neup.12797. PMC   9305503 . PMID   35026860.
  19. ↑ "WikiCrow | FutureHouse". wikicrow.ai. Retrieved 2025-12-18.
  20. 1 2 Tachikawa M, Kanagawa M, Yu CC, Kobayashi K, Toda T (March 2012). "Mislocalization of fukutin protein by disease-causing missense mutations can be rescued with treatments directed at folding amelioration". The Journal of Biological Chemistry. 287 (11): 8398–8406. doi: 10.1074/jbc.M111.300905 . PMC   3318729 . PMID   22275357.
  21. ↑ Holdbrook DA, Leung YM, Piggot TJ, Marius P, Williamson PT, Khalid S (December 2010). "Stability and membrane orientation of the fukutin transmembrane domain: a combined multiscale molecular dynamics and circular dichroism study". Biochemistry. 49 (51): 10796–10802. doi:10.1021/bi101743w. PMC   3005826 . PMID   21105749.
  22. ↑ Marius P, Wright JN, Findlow IS, Williamson PT (July 2010). "Expression and purification of the transmembrane domain of Fukutin-I for biophysical studies". Protein Expression and Purification. 72 (1): 107–112. doi:10.1016/j.pep.2010.01.019. PMC   2937224 . PMID   20117215.
  23. 1 2 Murakami T, Hayashi YK, Noguchi S, Ogawa M, Nonaka I, Tanabe Y, et al. (November 2006). "Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness". Annals of Neurology. 60 (5): 597–602. doi:10.1002/ana.20973. PMID   17036286.
  24. ↑ "Gene Therapy for Limb-Girdle Muscular Dystrophy Type 2i/R9 Receives Fast Track Designation - Practical Neurology". practicalneurology.com. Retrieved 2025-12-18.
  25. ↑ Bichat C (2023-10-27). "First clinical results of a Gene Therapy for the Treatment of Limb-Girdle Muscular Dystrophy presented at ESGCT Congress". Généthon. Retrieved 2025-12-18.
  26. ↑ 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.
  27. ↑ Yamamoto T, Okamura Y, Kato Y, Masui K, Nagasima Y, Kurata A (October 2025). "Suppressive role of fukutin on cell proliferation in uterine cervical carcinoma in relation to Aurora-A kinase". Histology and Histopathology. 40 (10): 1555–1568. doi:10.14670/HH-18-889. PMID   40034075.
  28. ↑ Yamamoto T, Kato Y, Shibata N, Sawada T, Osawa M, Kobayashi M (October 2008). "A role of fukutin, a gene responsible for Fukuyama type congenital muscular dystrophy, in cancer cells: a possible role to suppress cell proliferation". International Journal of Experimental Pathology. 89 (5): 332–341. doi:10.1111/j.1365-2613.2008.00599.x. PMC   2613979 . PMID   18808525.
  29. ↑ Spencer D (2022-12-13). "RNA interference method could treat muscular dystrophy". Drug Discovery World (DDW). Retrieved 2025-12-18.
  30. ↑ Takeda S, Kondo M, Sasaki J, Kurahashi H, Kano H, Arai K, et al. (June 2003). "Fukutin is required for maintenance of muscle integrity, cortical histiogenesis and normal eye development". Human Molecular Genetics. 12 (12): 1449–1459. doi:10.1093/hmg/ddg153. PMID   12783852. Archived from the original on 2025-04-18.
  31. ↑ "FKTN-related disorders Genetic Testing | Foresight® Carrier Screen". Myriad Women's Health. Retrieved 2025-12-19.
  32. ↑ Murakami T, Hayashi YK, Noguchi S, Ogawa M, Nonaka I, Tanabe Y, et al. (November 2006). "Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness". Annals of Neurology. 60 (5): 597–602. doi:10.1002/ana.20973. PMID   17036286.
  33. ↑ D'Souza AD. "Causes of FCMD | Muscular Dystrophy News" . Retrieved 2025-12-19.
  34. ↑ Lee SJ, Joo HJ, Jo DH, Jung JH, Lee K, Kim JH, et al. (November 2025). "Ophthalmologic manifestations associated with Fukutin (FKTN) variant subtypes in Korean patients with Fukuyama congenital muscular dystrophy: a single-center retrospective case series". BMC Ophthalmology. 25 (1) 616. doi: 10.1186/s12886-025-04432-x . PMC   12584371 . PMID   41188778.

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