DFNA5

DFNA5 (also known as GSDME) is a gene that plays a dual role in hearing function and apoptosis (programmed cell death), regulating auditory cell survival and contributing to tumor suppression. 

Mutations in DFNA5 are linked to autosomal dominant non-syndromic hearing loss (ADNSHL), while its epigenetic silencing has been observed in various cancers, highlighting its role in both disease progression and suppression.

What is DFNA5?

DFNA5 (Deafness, Autosomal Dominant 5), also known as GSDME (Gasdermin E), is a gene located on chromosome 7 that is essential in both hearing function and programmed cell death (apoptosis). 

The DFNA5 protein consists of two functional domains separated by a hinge region. The N-terminal domain induces apoptosis, while the C-terminal domain appears to regulate or suppress this activity. 

Under normal conditions, DFNA5 contributes to cellular homeostasis by controlling apoptosis, but specific mutations can either increase cell death (leading to hearing loss) or suppress it (as seen in certain cancers).

DFNA5 Mutations and Associated Conditions

The following conditions are associated with mutations in the DFNA5 gene: 

DFNA5 Non-Syndromic Hearing Loss

Nonsyndromic hearing loss is a type of hearing impairment that occurs without other medical conditions. It can range from mild to profound and may affect one or both ears. Unlike syndromic hearing loss, which is linked to additional health issues, nonsyndromic hearing loss affects only hearing.

Hearing loss can be inherited in different ways:

• Autosomal dominant (DFNA): passed down when one parent has the mutation.
• Autosomal recessive (DFNB): requires both parents to carry the mutation.
• X-linked (DFNX): affects males more severely and is passed through the X chromosome.
• Mitochondrial: passed down from the mother’s mitochondrial DNA.

Mutations in DFNA5 are primarily associated with autosomal dominant non-syndromic hearing loss (ADNSHL), characterized by:

• Postlingual Onset: hearing loss begins in adulthood (typically the third to fifth decade).
• Progressive Nature: the condition worsens over time.
• High-Frequency Hearing Loss: early symptoms include difficulty hearing high-pitched sounds.
• Autosomal Dominant Inheritance: affected individuals have a 50% chance of passing the mutation to offspring.

Nearly all known DFNA5 hearing loss mutations result in a truncated protein that induces aberrant apoptosis in auditory cells. Studies confirm this gain-of-function mechanism, where mutations directly trigger auditory cell death rather than causing hearing loss through haploinsufficiency.

DFNA5 and Cancer: A Tumor Suppressor Role

Beyond its role in hearing, DFNA5 functions as a tumor suppressor gene. Epigenetic silencing through methylation has been observed in multiple cancers, including gastric, colorectal, and breast cancer. Loss of DFNA5 expression in these cancers suggests it plays a role in apoptosis regulation and p53-mediated tumor suppression.

Molecular Pathways Involved

• Mitochondrial Dysfunction: DFNA5-related apoptosis is linked to mitochondrial oxidative stress.
• MAPK Pathway Activation: In HEK293T human cells, DFNA5 triggers ERK and JNK signaling, promoting apoptosis.
• Endoplasmic Reticulum (ER) Stress: DFNA5 mutations may disrupt protein sorting and folding, contributing to cell death.
• p53 Regulation: DFNA5 is a downstream target of p53, enhancing p53-mediated apoptosis in response to DNA damage.

Interestingly, in p53-deficient environments, DFNA5 can contribute to cell survival rather than apoptosis, indicating a context-dependent function in cancer biology.

Who Should Get DFNA5 Genetic Testing?

Genetic testing for DFNA5 is most appropriate for individuals with specific clinical presentations, including:

Adults with Progressive, Postlingual, High-Frequency Hearing Loss, Particularly with a Family History: a strong genetic component is suggested when multiple family members experience similar patterns of hearing decline.

Differentiating DFNA5 from Other Causes of Hearing Loss: since hearing loss can have multiple genetic and environmental causes, testing for DFNA5 can clarify whether a genetic mutation is responsible.

Genetic Counseling and Family Planning: a confirmed DFNA5 mutation has implications for family members, as it follows an autosomal dominant inheritance pattern. Pre- and post-test genetic counseling is essential to discuss the risks and implications for affected individuals and their relatives.

Test Procedure and Interpretation

Testing for DFNA5 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 DFNA5 genetic testing are considered to be without mutations that can alter the activity of the DFNA5 proteins.

Clinical Implications of Positive DFNA5 Mutations

The clinical implications of a positive DFNA5 mutation test result will vary by individual, although DFNA5 mutations in symptomatic patients may signal a need for further assessment and possibly treatment, especially in the setting of symptoms of nonsyndromic hearing loss.

Patients or practitioners with questions about the clinical implications of DFNA5 mutations should seek further assessment with a genetic counselor or expert. 

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