FKTN

The FKTN gene encodes fukutin, a crucial enzyme involved in the glycosylation of alpha-dystroglycan (α-DG), a protein that anchors muscle and brain cells to the surrounding extracellular matrix. 

Mutations in FKTN disrupt this process and lead to a spectrum of rare conditions known as dystroglycanopathies, ranging from severe congenital muscular dystrophy with brain abnormalities to milder forms of limb-girdle muscular dystrophy.

What is FKTN (Fukutin)?

FKTN is a gene located on chromosome 9q31.2 that provides instructions for making an enzyme called fukutin. Fukutin is essential for a process called glycosylation, where sugar molecules are added to proteins. 

This process is especially important for a protein called alpha-dystroglycan (α-DG), which helps muscle cells and brain cells attach properly to surrounding structures.

FKTN: A Key Player in Muscle and Brain Development

FKTN is important for proper muscle and brain functioning.

Gene and Protein

The FKTN gene encodes fukutin, a type II transmembrane glycosyltransferase located in the Golgi apparatus. It is most active in skeletal muscle, the brain, and the heart.

Role in Protein Modification

Fukutin helps add ribitol-5-phosphate to α-DG—a necessary step in the formation of functional glycan chains that allow α-DG to bind to proteins like laminin in the extracellular matrix.

Importance for Alpha-Dystroglycan

This glycosylation process allows α-DG to anchor cells to their external environment, especially in muscles and the central nervous system. Without proper glycosylation, α-DG can’t function correctly, leading to structural instability and muscle damage over time.

Disorders Caused by FKTN Mutations

Mutations in the FKTN gene are associated with a range of rare neuromuscular and cardiac disorders, each with varying degrees of severity and clinical features.

Fukuyama Congenital Muscular Dystrophy (FCMD)

Fukuyama Congenital Muscular Dystrophy (FCMD) is the most common FKTN-related disorder in Japan and is characterized by progressive muscle weakness, along with brain and eye abnormalities. 

Walker-Warburg Syndrome (WWS)

Walker-Warburg Syndrome (WWS) is a rare, severe congenital muscular dystrophy marked by brain malformations, eye abnormalities, muscle weakness, and early death, typically before age three. 

It is caused by defective glycosylation of α-dystroglycan, a protein essential for muscle and brain structure. 

Mutations in several genes can lead to WWS, including FKTN, which encodes fukutin. Fukutin is required for proper α-dystroglycan glycosylation, and FKTN mutations have been linked to WWS, as well as milder related disorders like Fukuyama congenital muscular dystrophy.

Limb-Girdle Muscular Dystrophy Type 2M (LGMD2M)

Limb-Girdle Muscular Dystrophy Type 2M (LGMD2M) is a milder form that primarily presents with proximal muscle weakness and generally spares cognitive function. 

Dilated Cardiomyopathy 1X (CMD1X)

Dilated Cardiomyopathy 1X (CMD1X) is another condition linked to FKTN mutations and involves isolated cardiac abnormalities, though it may sometimes appear as part of a broader muscular phenotype.

When is FKTN Genetic Testing Relevant?

FKTN genetic testing may be relevant in the following situations:

Suspected Fukuyama Congenital Muscular Dystrophy (FCMD)

Genetic testing for FKTN mutations is important when individuals show signs of:

• Poor muscle tone (hypotonia) in infancy
• Muscle weakness
• Intellectual disability or developmental delays
• Eye problems
• Brain abnormalities (e.g., cobblestone lissencephaly on MRI)

Family History of FCMD

Carrier testing can identify relatives at risk or inform reproductive planning for families with known FKTN mutations.

Other Muscular Dystrophies

When diagnosing muscular dystrophies with overlapping symptoms—such as limb-girdle muscular dystrophy—FKTN testing helps distinguish between similar genetic conditions.

Genetic Counseling

Pre- and post-test counseling is strongly advised to discuss inheritance patterns, carrier risks, and implications for children.

What Do Specific FKTN Mutations Mean?

FKTN mutations can have the following implications:

Genetic Diagnosis

Identification of a disease-causing (pathogenic) mutation confirms the diagnosis of FKTN-related dystroglycanopathy.

Inheritance

All known FKTN-associated conditions follow an autosomal recessive pattern—meaning both parents must carry a mutation for a child to be affected.

Genotype–Phenotype Correlation

Certain mutations lead to severe congenital disease (like FCMD or Walker-Warburg syndrome).

Others result in milder limb-girdle presentations (e.g., LGMD2M/LGMDR13).

Compound heterozygous mutations may produce variable severity depending on the mutation type.

What Does the Absence of Pathogenic FKTN Mutations Mean?

Other Genetic Conditions Still Possible

A negative FKTN test doesn’t rule out congenital muscular dystrophy. Dozens of genes can cause similar symptoms.

Broader Testing Recommended

Consider expanded testing if clinical suspicion remains high (e.g., multigene panels or exome sequencing).

Test Procedure and Interpretation

Testing for FKTN is often performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for FKTN genetic testing are considered to be without mutations that can alter the activity of the FKTN proteins.

Clinical Implications of Positive FKTN Mutations

The clinical implications of a positive FKTN mutation test result will vary by individual, although FKTN mutations in symptomatic patients may signal a need for further assessment and possibly treatment, especially in the setting of symptoms associated with muscle and nervous system symptoms.

Patients or practitioners with questions about the clinical implications of FKTN mutations should seek further assessment with a genetic counselor or expert. 

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