Dysferlin Protein: Key Roles, Genetic Locations

The purpose of this article is to share and discuss the details of a new discovery, which is highlighted within: CRISPR-Cas9: A Breakthrough Tool to Repair the DYSF Gene

The dysferlin protein plays an essential role in maintaining the integrity of muscle cell membranes, particularly in tissues that endure significant mechanical stress, such as skeletal and cardiac muscles. Encoded by the DYSF gene, dysferlin is indispensable for repairing damaged cell membranes after injury caused by muscle contraction or external forces. This article explores the main locations where dysferlin is produced, its role in muscle repair, and supportive nutritional and therapeutic strategies for individuals with dysferlin deficiency, such as those affected by dysferlinopathies (e.g., Limb-Girdle Muscular Dystrophy Type 2B or Miyoshi Myopathy).

Currently, there is no definitive answer as to why the severity of dysferlin protein expression or depletion varies. Do pathogens play a role in the methylation of the DYSF gene?
See: https://swaresearch.blogspot.com/2025/01/what-pathogens-could-be-involved-in.html

Key Locations Where Dysferlin Protein Is Produced

1. Skeletal Muscles (Primary Site)

Function: Dysferlin is most highly expressed in skeletal muscles, where it is critical for repairing the sarcolemma (muscle cell membrane). During normal muscle contractions and physical activity, small tears can occur in the sarcolemma. Dysferlin facilitates rapid membrane repair by mobilizing vesicles to seal these tears, protecting muscle fibers from further damage and inflammation.

Examples of Skeletal Muscles:

Quadriceps: Thigh muscles used in walking and running.
Deltoids: Shoulder muscles involved in arm movement.
Gastrocnemius: Calf muscles critical for standing and jumping.
Other muscles: Found throughout the body, enabling various movements.
The muscles that support the spinal cord primarily consist of deep and superficial muscles of the back and core, which stabilize and move the spine. These muscles work together to protect the spinal cord (which runs through the vertebral column) and maintain posture and movement.
1. Deep (Intrinsic) Back Muscles
These muscles are directly responsible for stabilizing and supporting the spine. They are also involved in movements like extension, rotation, and lateral bending of the spine.
Erector Spinae Group (Primary Spinal Extensors)
Iliocostalis (lateral group): Helps with extension and lateral bending of the spine.
Longissimus (middle group): Supports extension, lateral bending, and rotation.
Spinalis (medial group): Supports spinal extension and stabilization.

Transversospinalis Group (Deep Stabilizers)

These muscles are smaller and located deeper. They play a critical role in fine motor control, stabilization, and small rotational movements of the spine.

Semispinalis: Extends the spine and helps with rotation.
Multifidus: A critical stabilizer of the spinal column, particularly during movement.
Rotatores: Assists in rotation and stabilization of the spine.

Segmental Muscles

Interspinales: Connect adjacent vertebrae, aiding in extension and stability.
Intertransversarii: Stabilize and assist in lateral bending of the spine.

2. Superficial Back Muscles

While these muscles are not directly involved in stabilizing the spinal column itself, they provide additional support and facilitate movement of the spine, shoulders, and ribs.

Trapezius: Stabilizes and moves the scapula, indirectly supporting the upper spine.
Latissimus Dorsi: Supports posture by anchoring the lower spine and pelvis.
Rhomboid Major and Minor: Stabilize the scapula, aiding upper spinal support.
Levator Scapulae: Assists with neck movement and stabilization.

3. Core Muscles (Spinal Support from the Front and Sides)

The core muscles complement the back muscles to provide balanced spinal support.

Abdominal Muscles

Rectus Abdominis: Flexes the spine and helps stabilize the lumbar region.
Transversus Abdominis: A deep core muscle that acts like a "corset," compressing and stabilizing the spine.
Internal and External Obliques: Assist in rotation, lateral bending, and stabilization.

Pelvic Muscles

Pelvic Floor Muscles: Provide a base of support for the spine and pelvis.
Iliopsoas (Psoas Major and Iliacus): Stabilizes the lumbar spine and connects the spine to the lower body.

The rotation of the arm and hand involves several muscles that work together to facilitate movement at the shoulder, elbow, and wrist. These muscles enable movements such as supination (palm up) and pronation (palm down) of the forearm, as well as rotation at the shoulder joint. Below is a breakdown of the muscles involved:1. Shoulder Joint Rotation (Arm Rotation)
Rotation of the arm at the shoulder involves the rotator cuff muscles, along with other muscles that control the humerus (upper arm bone):
Internal Rotation (Medial Rotation of the Arm)
Subscapularis: The primary muscle for internal rotation of the arm.
Pectoralis Major: Assists in internal rotation.
Latissimus Dorsi: Assists in internal rotation and adduction.
Teres Major: Assists in internal rotation.
Anterior Deltoid: Helps with medial rotation of the shoulder.

External Rotation (Lateral Rotation of the Arm)

Infraspinatus: The primary external rotator of the arm.
Teres Minor: Works with infraspinatus for external rotation.
Posterior Deltoid: Assists with lateral rotation.

2. Forearm Rotation (Pronation and Supination)

Rotation of the forearm occurs at the radioulnar joints, enabling supination and pronation.

Supination (Palm Up)

Biceps Brachii: The main muscle for supination when the elbow is flexed.
Supinator: A deep muscle that assists in supination, particularly when the elbow is extended.

Pronation (Palm Down)

Pronator Teres: The primary muscle for pronation, located near the elbow.
Pronator Quadratus: A deep muscle near the wrist that helps with pronation.

3. Wrist and Hand Rotation (Complex Movements)

While the wrist does not rotate in isolation (rotation happens at the forearm), specific wrist and hand movements involve coordination of the following muscles:

Radial and Ulnar Deviation (Side-to-Side Movement of the Hand at the Wrist)

Flexor Carpi Radialis: Involved in wrist flexion and radial deviation.
Extensor Carpi Radialis Longus and Brevis: Involved in radial deviation and wrist extension.
Flexor Carpi Ulnaris: Involved in wrist flexion and ulnar deviation.
Extensor Carpi Ulnaris: Involved in wrist extension and ulnar deviation.

Fine Motor Control of Hand

While not directly related to rotation, intrinsic hand muscles (such as lumbricals and interossei) help stabilize and position the hand during rotational movements.

Summary

Shoulder Rotation: Subscapularis, infraspinatus, teres minor, etc.
Forearm Rotation: Biceps brachii, supinator, pronator teres, and pronator quadratus.
Wrist & Hand: Flexor and extensor carpi muscles for stabilization and deviations.

These muscles work in concert to allow the intricate rotational movements of the arm and hand.

4. Neck Muscles (Supporting the Cervical Spine)

The cervical spine is stabilized and moved by specific neck muscles:

Sternocleidomastoid: Stabilizes and rotates the head and neck.
Scalenes: Assist in cervical stability and lateral bending.
Suboccipital Muscles: Provide fine motor control and stabilization of the upper cervical spine.

Key Muscle for Core Spinal Support: Multifidus

Among all these muscles, the multifidus is particularly important for spinal stability. It lies deep along the spine, spanning multiple vertebrae, and plays a critical role in preventing excessive movement and protecting the spinal cord.

Summary

The muscles that support the spinal cord include:

Deep back muscles (erector spinae, transversospinalis, etc.).
Core muscles (transversus abdominis, obliques, rectus abdominis).
Superficial back muscles (trapezius, latissimus dorsi, etc.).
Pelvic floor muscles (psoas major, iliacus, etc.). These muscles work together to stabilize the vertebral column, maintain posture, and protect the spinal cord during movement and rest.

2. Cardiac Muscle

Function: Dysferlin is also produced in the cardiac muscle cells (cardiomyocytes) of the heart, which undergo constant mechanical stress due to continuous contractions. Dysferlin supports the structural integrity of cardiac muscle membranes, preventing damage caused by repetitive stress.

Clinical Note: Although dysferlinopathies typically spare the heart, dysferlin is still vital for maintaining cardiac function, and dysfunction can sometimes indirectly affect heart performance in specific cases.

3. Monocytes (A Type of White Blood Cell)

Function: Dysferlin is expressed in monocytes, immune cells circulating in the bloodstream. While its role in these cells is not fully understood, it is hypothesized to be involved in vesicle trafficking or immune regulation.

Clinical Importance: Measuring dysferlin levels in monocytes is a valuable diagnostic tool for identifying dysferlinopathies, offering a less invasive alternative to muscle biopsy.

4. Other Tissues (Low Levels of Expression)

Dysferlin is expressed in smaller amounts in tissues such as:

Lungs
Kidneys
Placenta

These tissues may use dysferlin for specialized cellular processes rather than membrane repair, as they do not experience the same mechanical stress as muscle tissues.

Cellular Production and Localization of Dysferlin

Production Process: Dysferlin is synthesized in the ribosomes of muscle cells, following transcription of the DYSF gene in the cell nucleus. After synthesis:

Dysferlin undergoes post-translational processing in the endoplasmic reticulum (ER) and Golgi apparatus, where it is folded and modified.
The functional protein is transported to the sarcolemma, where it performs its role in membrane repair.

Challenges in Addressing Dysferlin Deficiency

Dysferlinopathies, caused by mutations in the DYSF gene, result in insufficient or nonfunctional dysferlin, leading to impaired muscle membrane repair, chronic inflammation, and progressive muscle damage. Currently, there is no medication, supplement, or therapy that can fully replace or replicate dysferlin’s function. Emerging gene and molecular therapies offer hope for addressing the root cause of dysferlin deficiency, but supportive strategies can help mitigate symptoms and improve quality of life.

Types of Mutations in the DYSF Gene

To date, over 500 different mutations in the DYSF gene have been identified. These mutations include:

Missense Mutations: A single amino acid change in the dysferlin protein. These mutations often lead to reduced protein stability or impaired function.
Nonsense Mutations: Premature stop codons result in truncated, non-functional proteins.
Frameshift Mutations: Insertions or deletions that disrupt the reading frame and usually result in a nonfunctional protein.
Splice-Site Mutations: Alterations in the splicing of mRNA can lead to incorrect or missing regions in the dysferlin protein.
Large Deletions or Duplications: Structural variations in the DYSF gene that remove or add substantial portions of the gene.

The specific mutation can influence the severity of the disease and the age of onset, although there is variability even among individuals with the same mutation.

Reference SNP IDs (rs IDs) for common mutations in the DYSF gene, categorized by type (Missense, Nonsense, Frameshift, Splice-Site mutations). These rsIDs are from databases like ClinVar, dbSNP, and others that document genetic variants associated with dysferlinopathies:

1. Missense Mutations

Missense mutations result in a single amino acid change in the dysferlin protein. These mutations can disrupt protein folding or function. Examples of missense mutations in DYSF include:

rs1800261: Associated with p.Cys334Ser mutation.
rs121908040: Associated with p.Arg555Trp mutation.
rs749598695: Associated with p.Arg2042Cys mutation.
rs80338856: Associated with p.Arg1674Gln mutation.

2. Nonsense Mutations

Nonsense mutations introduce a premature stop codon, leading to truncated, non-functional dysferlin protein. Examples include:

rs398123165: Associated with p.Gln2064Ter mutation (Glutamine to stop codon).
rs80338857: Associated with p.Arg1110Ter mutation (Arginine to stop codon).
rs863224768: Associated with p.Trp999Ter mutation (Tryptophan to stop codon).

3. Frameshift Mutations

Frameshift mutations result from insertions or deletions of nucleotides that shift the reading frame of the gene, often leading to a completely non-functional protein. Examples include:

rs398123162: Associated with p.Leu1341ProfsTer2 (frameshift caused by a deletion).
rs80338859: Associated with p.Ser267PhefsTer24 (frameshift caused by an insertion).
rs770273512: Associated with p.Gly302ValfsTer43 (frameshift caused by deletion).

4. Splice-Site Mutations

Splice-site mutations affect how the mRNA is spliced, leading to improper exon inclusion or exclusion. Examples include:

rs80338858: Associated with a splice donor site mutation in intron 34.
rs794727646: Affects splicing at intron 19, leading to exon skipping.
rs80338855: Mutation at the splice acceptor site of intron 44. Example: (https://www.ncbi.nlm.nih.gov/medgen/C0175694) or: https://www.omim.org/entry/270400
RS ID (Reference SNP ID) for the DYSF variants p.Leu1341Pro and p.Val67Asp,

Example: The Dopamine D4 receptor gene, DRD4 (Varview rs752306 and rs587776842), is also associated with Dysferlinopathy. https://www.ncbi.nlm.nih.gov/books/NBK1303/

Excerpt: Dysferlinopathy: Included Phenotypes

Miyoshi muscular dystrophy (Miyoshi myopathy)
Limb-girdle muscular dystrophy type 2B
Asymptomatic hyperCKemia
Distal myopathy with anterior tibial onset

In addition: dermatomyositis, polymyositis, and dysferlinopathy

The PPI network and MCODE cluster identified 23 genes related to type 1 interferon signaling pathway in DM, 4 genes (PDIA3 (chromosome 15), HLA-C (chromosome 6), B2M (chromosome 15), and TAP1 (chromosome 6) related to MHC class 1 formation and quality control in PM, and 7 genes (HSPA9 (chromosome 5), RPTOR (chromosome 17), MTOR (chromosome 1), LAMTOR1 (chromosome 11), LAMTOR5 (chromosome 1) , ATP6V0D1(chromosome 16) , and ATP6V0B (chromosome 1) related to cellular response to stress in dysferlinopathy.

Notes:

The specific effects of these mutations can vary based on their location in the gene and the downstream consequences for dysferlin protein structure or function.
Variants like these have been identified through patient studies and large-scale genomic databases. They are often classified based on their pathogenicity (e.g., "pathogenic," "likely pathogenic," or "benign").

For further details about any specific rsID or variant, databases like ClinVar, dbSNP, or Ensembl can be queried for comprehensive annotations and associated clinical information.

Why Supplements Cannot Replace Dysferlin

The unique role of dysferlin in membrane repair cannot be replicated by dietary supplements or lifestyle changes. Dysferlin binds to calcium and mobilizes vesicles to "patch" damaged sarcolemma. Without dysferlin, this repair process fails, leading to cumulative muscle damage. Supplements, while beneficial for reducing inflammation and oxidative stress, do not address the underlying genetic defect.

Emerging Therapies for Dysferlin Deficiency

Research is ongoing to develop targeted therapies that address the root cause of dysferlinopathies:

Gene Therapy: Introducing a healthy copy of the DYSF gene to restore dysferlin production.
CRISPR-Cas9 Gene Editing: Correcting mutations in the DYSF gene to enable natural dysferlin production.
Stem Cell Therapy: Using genetically corrected muscle stem cells to replace damaged tissue.
Small Molecules: Developing drugs that compensate for dysferlin deficiency or enhance residual function.

How Dysferlin Mutation Leads to Sarcolemma Malfunction and Muscle Degeneration

Dysferlin’s Role in Membrane Repair

Dysferlin is a membrane-associated protein primarily found in skeletal muscle fibers, where it plays a crucial role in repairing the sarcolemma (the muscle cell membrane). During muscle contraction, small tears can form in the sarcolemma. Normally, dysferlin helps recruit intracellular vesicles to seal these tears, maintaining membrane integrity and preventing further muscle damage.

Impact of Dysferlin Mutation on Sarcolemma Function

Mutations in the DYSF gene lead to a deficiency or dysfunction of dysferlin, which disrupts this repair process. Without functional dysferlin:

Repair vesicles cannot fuse properly with the sarcolemma, leaving membrane damage unsealed.
This results in persistent membrane injury, making muscle cells highly vulnerable to mechanical stress.
Ions, particularly calcium, leak into the cell uncontrollably, leading to downstream cellular damage.

Consequences of Sarcolemma Dysfunction

Increased Calcium Influx
- The unsealed sarcolemma allows excess calcium to enter the muscle cell.
- High intracellular calcium activates proteases (e.g., calpains), which degrade key muscle proteins, accelerating muscle fiber damage.
Chronic Muscle Fiber Damage
- With each contraction, damage accumulates, leading to progressive muscle fiber deterioration.
Inflammation and Immune Response
- Damaged muscle fibers release distress signals, attracting immune cells.
- This triggers chronic inflammation, which further exacerbates muscle degeneration and promotes replacement of muscle tissue with fat and fibrosis.

Resulting Muscle Diseases

Since dysferlin is essential for sarcolemma repair, its dysfunction leads to progressive muscle weakness seen in dysferlinopathy-related muscular dystrophies, including:

Limb-Girdle Muscular Dystrophy Type 2B (LGMD2B)
Miyoshi Myopathy (MM)

Affected individuals experience muscle atrophy, weakness, and loss of function over time, particularly in limb and distal muscles.

https://www.youtube.com/watch?v=NvV2xTrShvg

Key Takeaway

Dysferlin mutation disrupts the sarcolemma’s repair mechanism, leading to chronic membrane damage, calcium overload, inflammation, and progressive muscle degeneration. These pathological changes drive the progression of LGMD2B and other dysferlin-related muscular dystrophies. Sarcoplasmic Reticulum and T Tubules https://www.youtube.com/watch?v=NvV2xTrShvg&t=31s

The interaction between sodium (Na⁺), calcium (Ca²⁺), and the sarcolemma is essential for muscle contraction and relaxation.
Na⁺ influx depolarizes the sarcolemma, triggering voltage-gated Ca²⁺ channels to open. In skeletal muscle, this activates ryanodine receptors (RyR1) to release Ca²⁺ from the sarcoplasmic reticulum (SR), while in cardiac muscle, Ca²⁺ influx triggers further Ca²⁺ release via RyR2. Ca²⁺ then binds to troponin, initiating contraction. After contraction, the Na⁺/Ca²⁺ exchanger (NCX) and Ca²⁺ pumps remove excess Ca²⁺, allowing relaxation. Proper Na⁺ and Ca²⁺ balance is crucial for maintaining normal muscle and cardiac function.

Conclusion

Dysferlin is primarily produced in skeletal and cardiac muscle cells, where it plays a critical role in membrane repair. While no dietary supplement can replace dysferlin, a combination of antioxidants, anti-inflammatory nutrients, amino acids, and a balanced diet can support muscle health and slow the progression of symptoms in dysferlinopathies. Addressing dysferlin deficiency ultimately requires advanced therapies such as gene editing or gene therapy.

Reference:

DYSdysferlin: https://www.ncbi.nlm.nih.gov/gene/8291

DYSF gene: https://medlineplus.gov/genetics/gene/dysf/

Transcriptome analysis of skeletal muscle in dermatomyositis, polymyositis, and dysferlinopathy, using a bioinformatics approach
https://pmc.ncbi.nlm.nih.gov/articles/PMC10731051/