GJB1

The GJB1 gene encodes connexin 32 (Cx32), a gap junction protein critical for direct cell-to-cell communication, particularly in myelinating cells of the peripheral and central nervous systems. 

Mutations in GJB1 cause X-linked Charcot-Marie-Tooth disease type 1 (CMT1X), a hereditary neuropathy characterized by muscle weakness, sensory loss, and variable involvement of the central nervous system.

What is GJB1 (Gap Junction Protein Beta 1)?

The GJB1 gene encodes a protein called connexin 32 (Cx32). This protein is a vital part of gap junctions, channels connecting neighboring cells. These channels allow ions, nutrients, and signaling molecules to pass directly from one cell to another, essential for healthy nerve function.

GJB1: The Gene Encoding Connexin 32 (Cx32)

Gene Location: X chromosome

Protein Product: Connexin 32 (Cx32)

Tissue Expression: Nervous system (Schwann cells and oligodendrocytes), liver, pancreas, and kidney

Connexin 32 is especially important in myelinating Schwann cells of the peripheral nervous system (PNS) and plays a supporting role in oligodendrocytes in the central nervous system (CNS).

Gap Junctions and Intercellular Communication

Gap junctions are formed when two connexons (hemichannels) from adjacent cells dock together. Each connexon is made of six connexin proteins. 

These structures allow fast and direct cell-to-cell communication by letting small molecules and ions pass freely.

Role in Myelinating Cells (Schwann Cells)

In the PNS, Schwann cells wrap around axons to form the myelin sheath, which insulates nerves and speeds up signal transmission. 

Connexin 32 is found in specific regions of Schwann cells—especially in non-compact myelin areas like the Schmidt-Lanterman incisures and paranodes—where it helps maintain the health of the myelin sheath by allowing communication between the inner and outer layers of the cell.

Clinical Implications of GJB1 Mutations: Charcot-Marie Tooth Disease, Type X1

Charcot-Marie-Tooth disease (CMT) is the most common inherited condition that affects the nerves. It causes weakness and shrinking of muscles, especially in the lower legs and feet, along with numbness or loss of feeling. 

People often start noticing symptoms in childhood or teenage years, and the condition usually progresses slowly over time.

Types and Causes

There are several types of CMT, grouped based on how the nerves are damaged:

• CMT1: Caused by damage to the protective covering (myelin) around nerves. It’s often due to PMP22, MPZ, or GJB1 gene mutations.
• CMT2: Caused by damage to the nerve fibers themselves (the axons). It’s often linked to changes in the MFN2 gene.
• CMTX: A form of CMT that is passed down through the X chromosome. Mutations in the GJB1 gene most often cause it (over 400 mutations have been identified), and it usually affects males more severely than females.

Over 100 genes have been linked to CMT, but most cases are due to just a few key genes.

The GJB1 Gene and CMTX1

GJB1 genetic mutations cause CMTX1, an X-linked form of CMT. In this type:

• Boys and men often have more serious symptoms because they only have one X chromosome.
• Nerve signals may slow down differently in different parts of the body.
• Some people may also have hearing loss or changes in their pupils.
• Females can have mild or no symptoms, but sometimes the condition still affects them.

Some GJB1 mutations will include, or primarily manifest with, CNS symptoms.

How CMT Is Diagnosed

Doctors diagnose CMT by:

• Asking about symptoms and family history.
• Nerve tests (EMG and nerve conduction studies) to see how fast and strong the nerve signals are.
• Genetic testing to look for the most common gene mutations, including GJB1.

Treatment and Support

There is no cure for CMT yet, but treatment can help manage the symptoms. Treatment may include:

• Physical and occupational therapy to stay strong and improve movement.
• Braces or special shoes to help with walking and prevent falls.
• Medications for pain if needed.
• Genetic counseling to help families understand the condition and plan for the future.

Some people may be able to join clinical trials that test new treatments.

Outlook

CMT usually does not shorten life, but it can affect a person’s ability to walk, work, or do everyday activities. How fast it gets worse depends on the type and when symptoms begin. 

With the right care and support, many people with CMT can lead full and active lives.

When is GJB1 Genetic Testing Relevant?

Genetic testing for GJB1 mutations may be appropriate in the following settings: 

Clinical Suspicion of Charcot-Marie-Tooth Disease Type 1X (CMT1X)

GJB1 mutations are a common cause of CMT1X, an inherited peripheral neuropathy. Testing is appropriate for individuals with:

• Distal muscle weakness and atrophy (hands and feet)
• Sensory loss
• Foot deformities (e.g., high arches or pes cavus)
• Symptoms beginning in childhood, adolescence, or early adulthood

Family History of CMT

CMT1X follows an X-linked inheritance pattern. Males who inherit a pathogenic GJB1 mutation typically develop symptoms of the disease because they have only one X chromosome. 

In contrast, females who carry the mutation on one of their two X chromosomes may be carriers. Due to a process called X-inactivation, carrier females may show mild symptoms or remain asymptomatic. 

Genetic testing is valuable in families with a history of CMT, as it can confirm carrier status in females and help assess the risk of passing the mutation to children.

Differentiating CMT Subtypes

CMT has multiple genetic causes. GJB1 testing helps distinguish CMT1X from other CMT types and acquired neuropathies.

Genetic Counseling

Genetic counseling is recommended before and after testing to explain inheritance patterns, interpret results, and guide family planning.

GJB1 Genetic Testing: Test Procedure and Interpretation

Testing for GJB1 is 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 GJB1 genetic testing are considered to be without mutations that can alter the activity of the GJB1 proteins.

What Does the Presence of Specific GJB1 Mutations Mean?

Specific GJB1 mutations may have the following clinical significance:

Pathogenic Mutations Confirm CMT1X

Identifying a pathogenic (disease-causing) mutation in the GJB1 gene confirms a diagnosis of CMT1X in males and carrier status in females. This is a key step in providing an accurate diagnosis and guiding management for affected individuals and their families.

X-Linked Inheritance

CMT1X is inherited in an X-linked manner. Males who carry a GJB1 mutation (hemizygous) typically show the classic symptoms of the disorder, such as progressive muscle weakness and sensory loss. Males will pass on the affected gene to all daughters, but no sons. 

Females with a mutation (heterozygous) may have milder symptoms or may not show any symptoms at all, depending on how the mutation is expressed due to X-chromosome inactivation. 

Carrier females have a 50% chance of passing on the affected gene to offspring.

Genotype-Phenotype Correlation

Severity and symptoms can vary based on the specific GJB1 mutation. Some variants cause only peripheral symptoms; others may involve the CNS.

What Does the Absence of Pathogenic GJB1 Mutations Mean?

The absence of pathogenic variants means that GJB1 mutations are not the cause of observed symptoms. A negative test result may also carry the following significance:

Does Not Exclude CMT

A negative result does not rule out inherited neuropathy. Other genes may be involved.

Consider Broader Testing

If clinical suspicion remains high, wider testing, such as expanded genetic panels or whole exome/genome sequencing, should be considered.

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