FKRP

The FKRP (Fukutin-Related Protein) gene encodes a glycosyltransferase essential for proper muscle and brain function by modifying α-dystroglycan. 

Mutations in FKRP disrupt this glycosylation process, leading to a group of disorders known as dystroglycanopathies. These disorders range from mild muscular dystrophy to severe congenital conditions affecting the brain and eyes.

What is FKRP (Fukutin-Related Protein)?

The FKRP gene encodes the fukutin-related protein, a glycosyltransferase located in the Golgi apparatus. 

It is highly expressed in skeletal muscle, cardiac muscle, and the brain, where it modifies α-dystroglycan (α-DG) by adding ribitol 5-phosphate. This step in glycosylation is essential for α-DG’s ability to anchor muscle cells to surrounding tissues and guide neuron development during early brain formation.

FKRP: A Key Player in Muscle Function

The following sections describe the normal function of the protein associated with the FKRP gene.

Gene and Protein

FKRP helps build and maintain muscle integrity by supporting the glycosylation of α-dystroglycan, a protein that forms a structural bridge between the cell’s internal framework and the extracellular matrix.

Muscle Cells and Brain Development

Properly glycosylated α-dystroglycan is vital for the strength and stability of skeletal and cardiac muscle fibers. It also plays a role in neuron migration during early brain development.

Glycosylation Matters

Without FKRP function, α-dystroglycan is improperly glycosylated, leading to unstable muscle fibers and a spectrum of conditions called dystroglycanopathies, which range from mild muscle weakness to severe congenital syndromes affecting the brain and eyes.

When is FKRP Genetic Testing Relevant?

The following scenarios may prompt FKRP genetic testing:

Suspected Muscular Dystrophy

Consider testing in patients with:

• Progressive proximal muscle weakness, especially in the hips and shoulders.
• Elevated creatine kinase (CK) levels.
• Muscle biopsy suggestive of dystrophic changes or reduced α-DG glycosylation.

Family History of FKRP Mutations

Genetic testing can identify carriers and help guide family planning decisions in families with a known FKRP-related disorder.

Distinguishing from Other Disorders

FKRP testing aids in differentiating dystroglycanopathies from similar muscular dystrophies, including Duchenne and Becker.

Genetic Counseling

Due to its autosomal recessive inheritance, counseling is essential for understanding risk, interpreting results, and managing family implications.

What Do Specific FKRP Mutations Mean?

Specific FKRP mutations may provide important information about:

Diagnostic Confirmation

Identifying pathogenic variants confirms a diagnosis of FKRP-related muscular dystrophy.

Inheritance Pattern

Most FKRP disorders follow an autosomal recessive pattern. Both parents must be carriers for a child to be affected.

Genotype-Phenotype Correlations

• Homozygous c.826C>A (p.Leu276Ile) is common in European populations and associated with milder, slower-progressing disease.
• Compound heterozygotes and rare variants are usually linked to earlier onset and more severe decline.
• Some variants may cause brain and eye malformations, as seen in Walker-Warburg syndrome or muscle–eye–brain disease.

What Does the Absence of Pathogenic FKRP Mutations Mean?

A negative FKRP test does not rule out muscular dystrophy. Other genes can cause similar symptoms. If clinical suspicion remains high, consider:

• Exome sequencing
• Targeted muscular dystrophy panels

Test Procedure and Interpretation

Testing for FKRP 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 FKRP genetic testing are considered to be without mutations that can alter the activity of the FKRP proteins.

Clinical Implications of Positive FKRP Mutations

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

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

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