FKTN
protein-codingfukutin
Gene summary
The protein encoded by this gene is a putative transmembrane protein that is localized to the cis-Golgi compartment, where it may be involved in the glycosylation of alpha-dystroglycan in skeletal muscle. The encoded protein is thought to be a glycosyltransferase and could play a role in brain development. Defects in this gene are a cause of Fukuyama-type congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), limb-girdle muscular dystrophy type 2M (LGMD2M), and dilated cardiomyopathy type 1X (CMD1X). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2010]
- FCMD
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~95.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0012699
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009678
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0018276
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0000171
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012699
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009678
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012704
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0015470
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012704
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0018279
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0700067
Submitter: ClinGen
The relationship between *FKTN* and myopathy caused by variation in FKTN (muscular dystrophy-dystroglycanopathy types 4A, 4B and 4C and dilated Cardiomyopathy 1X included) inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of June, 2020. This association was made using case-level and experimental data. The *FKTN* gene is located on chromosome 9q31.2 and encodes multiple transcript variants. The commonly referred transcript (NM_001079802.2) is 7.4 kb long with 10 exons encoding a 461-amino acid protein. More than 70 pathogenic variants reported in humans with autosomal recessive myopathy caused by variation in FKTN are recorded in ClinVar, ranging from small deletions and duplications, nonsense, frameshift and splicing to missense variants. Myopathy caused by variation in FKTN encompasses a spectrum of phenotypes including severe forms with muscle-eye-brain disease, Fukuyama-type congenital muscular dystrophy and Walker-Warburg syndrome and milder forms of muscular dystrophy dystroglycanopathy without intellectual disability, limb-girdle muscular dystrophy and cardiomyopathy. Patients often show an elevated serum creatine kinase and progressive muscle weakness. *FKTN* has been reported in association with autosomal recessive myopathy caused by variation in FKTN as early as 1998 by Kobayahsi et al (PMID: 9690476). OMIM entities: Cardiomyopathy, dilated, 1X, (MIM# 611615); Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 (MIM# 253800); Muscular dystrophy-dystroglycanopathy (congenital without mental retardation), type B, 4 (MIM# 613152); Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 4 (MIM# 611588). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) AND inheritance pattern AND phenotypic variability in the above mentioned disease entities. Therefore, all of the disease entities were originally lumped into one disease entity, “myopathy caused by variation in FKTN”. In order to improve the consistency of the nomenclature relating to qualitative or quantitative defects of proteins involved in O-glycosylation of alpha-dystroglycan and better represent the spectrum of phenotypes associated with variation in these genes, the LGMD GCEP proposed the nomenclature revision: myopathy caused by variation in **gene**. Summary of Case Level Data (12 points): The association is seen in at least 9 probands in 6 publications (PMID: 12601708, 19396839, 17036286, 9690476, 17044012, 14627679). The Japanese founder variant, a 3-kb retrotransposon insertion in the 3'UTR of *FKTN* is frequently reported and patients homozygous for this variant show a milder phenotype compared to patients compound heterozygous with a null variant (PMID: 9690476, 17036286). *FKTN* variants have also been identified in patients with dilated cardiomyopathy and only mild or subclinical skeletal muscle involvement (PMID: 17036286). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease is expected to be biallelic loss of function. Summary of Experimental Data (6 points): This gene-disease relationship is supported by animal models, expression studies, functional assays and rescue evidence. Fukutin is localized to the Golgi and has a role the glycosylation of alpha-dystroglycan in skeletal muscle and may be involved in brain development (PMID: 9690476, 21979053, 17034757). It is expressed in skeletal muscles, brain and retina (PMID: 9690476, 10852541). Fukutin interacts with other members involved in the process of dystroglycan glycosylation (PMID: 29477842, 17005282). Many model organisms have been developed including mouse and zebrafish models (PMID: 22922256, 19017726, 21317159) and rescue in mouse models and patient cells (PMID: 21979053) are also reported. In summary, *FKTN* - myopathy caused by variation in FKTN gene-disease relationship is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was originally approved by the ClinGen Limb-Girdle Muscular Dystrophy GCEP on July 1st, 2020 (SOP Version 7), but has since been updated to reflect SOP V9 (June 19, 2023). Data provided by the ClinGen Prenatal GCEP from October 21, 2025 secondary analysis: Prenatal detection of congenital anomalies in fetuses with myopathy caused by variation in FKTN has been reported in a small number of cases, primarily affecting the central nervous system. Specific anomalies that have been reported prenatally include cerebral ventriculomegaly (often severe), cerebellar anomalies, lissencephaly, abnormalities of the corpus callosum, abnormalities of the brainstem, renal anomalies, eye anomalies, and growth restriction (PMID: 19266496, 20961758, 25814170, 28749478, 31641664, 31756055, 33200426, 35843586).
Inheritance Pattern: AR
Disease ID:MONDO:0009678
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0018939
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012699
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0700067
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0009678
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Musculoskeletal; Neurologic; Ophthalmologic
Intervention: Cardiovascular; Musculoskeletal
Rationale: Surveillance for cardiovascular complications may allow early diagnosis and treatment, which may ameliorate morbidity and mortality; Cardiomyopathy, dilated, 1X has been reported as being treated with transplant; Individuals with Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 4 has been reported as benefiting from treatment with steroids
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FKTN variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001079802.2. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 6 | 207 | 1 | 215 | |
| missense | 1 | 19 | 374 | 14 | 2 | 410 |
| nonsense | 22 | 29 | 1 | 52 | ||
| start loss | 1 | 1 | 2 | |||
| frameshift | 33 | 57 | 7 | 97 | ||
| splice donor/acceptor (+/-2bp) | 2 | 27 | 7 | 36 | ||
| Total | 58 | 134 | 396 | 221 | 3 | 812 |
Highest pathogenic variant AF is 0.00018370761
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001073270.1 | 9 | MANE Select | |
| Ensembl | ENSP00000350687.6 | 9 | MANE Select | |
| RefSeq | NP_001185892.1 | 10 | Standard | |
| RefSeq | NP_001338425.1 | 9 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| fktn | Danio rerio | Structure: ocular blood vessel Quality: deformed abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Mannose type O-glycan biosynthesis - Homo sapiens (human)
Biological Process
- protein O-linked glycosylation
- nervous system development
- muscle organ development
- negative regulation of cell population proliferation
- protein O-linked mannosylation
Molecular Function
- protein binding
- transferase activity
Cellular Component
- extracellular space
- nucleus
- endoplasmic reticulum
- Golgi apparatus
- cis-Golgi network
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000223528
- Coding exons
- 9
- Length
- 82989
- Individuals with no LoFs
- 125569
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 179
- Defined
- 125748
- p
- 0.000712
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.0466 | 239 | 237 | 1.01 | 0.0000123 | 3051 |
| Missense (PolyPhen) | 60 | 62.521 | 0.95968 | 808 | ||
| Synonymous | 1.24 | 72 | 86.7 | 0.830 | 0.00000461 | 836 |
| Loss of Function | 2.18 | 14 | 26.0 | 0.538 | 0.00000141 | 299 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00031 | 0.00031 | rare |
| Latino/Admixed American | 0.0013 | 0.0013 | notable |
| Ashkenazi Jewish | 0.0079 | 0.0079 | notable |
| East Asian | 0.00038 | 0.00038 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00023 | 0.00023 | rare |
| South Asian | 0.00042 | 0.00042 | rare |
| Other | 0.00066 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Glycosyltransferase involved in the biosynthesis of the phosphorylated O-mannosyl trisaccharide (N-acetylgalactosamine- beta-3-N-acetylglucosamine-beta-4-(phosphate-6-)mannose), a carbohydrate structure present in alpha-dystroglycan (DAG1). Required for normal location of POMGNT1 in Golgi membranes, and for normal POMGNT1 activity (PubMed:17034757). May interact with and reinforce a large complex encompassing the outside and inside of muscle membranes. Could be involved in brain development. {ECO:0000269|PubMed:17034757, ECO:0000269|PubMed:25279699}.;
- Disease
- DISEASE: Muscular dystrophy-dystroglycanopathy congenital without mental retardation B4 (MDDGB4) [MIM:613152]: An autosomal recessive disorder characterized by congenital muscular dystrophy and evidence of dystroglycanopathy. Features included increased serum creatine kinase, generalized weakness, mild white matter changes on brain MRI, and absence of mental retardation. {ECO:0000269|PubMed:14627679, ECO:0000269|PubMed:18177472, ECO:0000269|PubMed:19179078, ECO:0000269|PubMed:19299310}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Muscular dystrophy-dystroglycanopathy limb-girdle C4 (MDDGC4) [MIM:611588]: An autosomal recessive degenerative myopathy characterized by progressive weakness of the pelvic and shoulder girdle muscles, and elevated serum creatine kinase. MDDGC4 has no brain involvement and a remarkable clinical response to corticosteroids. {ECO:0000269|PubMed:17044012, ECO:0000269|PubMed:19342235}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, dilated 1X (CMD1X) [MIM:611615]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:17036286}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.389
Intolerance Scores
- LoFtool
- 0.322
- RVIS EVS
- 0.58
- RVIS percentile EVS
- 82.25
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.479
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |