DNM2

Dynamin 2 (DNM2) is a GTPase protein that plays a crucial role in membrane remodeling, intracellular trafficking, and cell division. 

Mutations in the DNM2 gene are associated with neuromuscular disorders such as centronuclear myopathy (CNM) and Charcot-Marie-Tooth disease, intermediate type B (CMTIB), both of which impact muscle and nerve function.

What is DNM2 (Dynamin 2)?

Dynamin 2 (DNM2) is an important protein in membrane-related cellular processes. It belongs to the dynamin family of large GTPase proteins, which regulate essential cellular functions, including:

• Endocytosis: the process by which cells internalize substances from their surroundings.
• Cytokinesis: the final step of cell division, ensuring proper separation of daughter cells.
• Intracellular Trafficking: the movement of vesicles and proteins within the cell.

The DNM2 gene is located on chromosome 19 and encodes the dynamin 2 protein. Mutations in this gene are linked to several inherited disorders, particularly those affecting muscle and nerve function.

DNM2 Mutations and Associated Disorders

Pathogenic DNM2 mutations have been identified in two primary neuromuscular conditions:

Centronuclear Myopathy (CNM)

CNM is an autosomal dominant condition involving a group of congenital myopathies (muscle disorders present from birth) characterized by abnormal nuclear positioning within muscle fibers. 

Key clinical features include:

• Muscle weakness, typically affecting proximal muscles.
• Hypotonia (low muscle tone) often detected in infancy.
• Delayed motor milestones (e.g., sitting, walking).
• Skeletal abnormalities such as spinal curvature.

Charcot-Marie-Tooth Disease, Intermediate Type B (CMTIB)

Charcot-Marie-Tooth disease is a hereditary peripheral nerve disorder leading to progressive muscle weakness and sensory loss in the hands and feet. While DNM2 mutations affecting CNM typically involve gain-of-function, CMT mutations often lead to loss-of-function.

It is associated with:

• Foot deformities (e.g., high arches, pes cavus).
• Distal muscle weakness, typically appearing in adolescence or early adulthood.
• Sensory impairments, including numbness and tingling.
• Slower nerve conduction velocities on electromyography (EMG).

Who Should Get DNM2 Genetic Testing?

Genetic testing for DNM2 mutations is recommended in several clinical scenarios:

• Patients with progressive muscle weakness, hypotonia, or neuropathy suggestive of CNM or CMT.
• Individuals with a family history of DNM2-related disorders.
• Patients with muscle biopsy findings (e.g., centralized nuclei in muscle fibers) indicating CNM.

Genetic counseling is essential before and after testing to discuss inheritance patterns and reproductive risks.

Test Procedure and Interpretation

Testing for DNM2 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 DNM2 genetic testing are considered to be without mutations that can alter the activity of the DNM2 proteins.

Clinical Implications of Positive DNM2 Mutations

The clinical implications of a positive DNM2 mutation test result will vary by individual, although DNM2 mutations in symptomatic patients may signal a need for further assessment and possibly treatment, especially in the setting of various symptoms.

Patients or practitioners with questions about the clinical implications of DNM2 mutations should seek further assessment with a genetic counselor or expert. 

Clinical Implications of Negative DNM2 Mutations

A negative DNM2 test does not rule out all genetic causes of neuromuscular disease. Consider the following:

Other genes may be involved: many different genes can contribute to myopathies and neuropathies. If clinical suspicion remains high, expanded genetic testing panels should be considered.

Further testing may be needed: muscle biopsies, nerve conduction studies, and next-generation sequencing (NGS) panels may help identify alternative genetic causes.

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