IKBKAP

The IKBKAP gene, also known as ELP1, provides instructions for making the IKAP protein, a vital part of the Elongator complex that helps regulate gene transcription and support nerve cell development. 

Mutations in IKBKAP disrupt neuronal growth and survival, leading to familial dysautonomia (FD), a serious disorder affecting sensory and autonomic nervous system function.

What is IKBKAP (Inhibitor of Kappa Light Polypeptide Gene Enhancer in B-cells, Kinase Complex-Associated Protein)?

The IKBKAP gene, also called ELP1, provides instructions for making a protein known as IKAP (IκB kinase-associated protein) or elongator complex protein 1.

IKAP is a key subunit of the Elongator complex, which plays a major role in helping RNA polymerase II move along DNA during transcriptional elongation — a critical step in turning genes into proteins.

Although originally linked to NF-κB signaling, research now shows that IKBKAP’s role is much broader. It helps regulate gene transcription, tRNA modification, histone acetylation, cytoskeletal organization, and cell migration, especially in nerve cells.

IKAP is especially important for the growth, survival, and function of sensory and autonomic neurons — the nerve cells responsible for sensing pain, controlling blood pressure, digestion, and body temperature.

IKBKAP: A Scaffold Protein Involved in Transcriptional Elongation

IKBKAP acts as a scaffold that helps assemble and stabilize the Elongator complex. This complex modifies proteins like histones and tRNAs, influencing how genes are expressed and how cells, particularly nerve cells, grow and survive.

In the nervous system, IKBKAP ensures proper development of nociceptors (pain-sensing neurons) and autonomic neurons (those that regulate involuntary body functions).

Without enough functional IKAP, certain sensory neurons die off or fail to mature properly, leading to serious neurological problems.

IKBKAP Gene and Protein and Familial Dysautonomia

Familial dysautonomia (FD) — also known as Hereditary Sensory and Autonomic Neuropathy Type III (HSAN III) or Riley-Day syndrome — is a rare genetic disorder that affects the development and survival of sensory and autonomic neurons. 

Symptoms begin at birth and worsen over time, including:

• Poor blood pressure and temperature regulation
• Reduced sensitivity to pain and temperature
• Swallowing problems, frequent vomiting, and lung infections
• Vision loss from optic nerve damage
• Balance problems, weak muscles, and delayed growth

Mutations in the IKBKAP gene cause FD, which encodes the IKAP protein. A common splicing mutation in FD leads to low IKAP levels, especially in neurons, causing nervous system dysfunction.

FD is inherited in an autosomal recessive pattern, meaning a child must inherit two faulty copies of the gene. It is most common in individuals of Ashkenazi Jewish descent, where carrier screening is recommended.

Genetic testing confirms the diagnosis by finding two pathogenic IKBKAP/ELP1 variants. While there is no cure, treatment focuses on managing symptoms, and research is ongoing to restore functional IKAP protein.

When is IKBKAP Genetic Testing Relevant?

Genetic testing for IKBKAP mutations is important when a person shows signs of familial dysautonomia (FD), including:

• Gastrointestinal issues (feeding problems, vomiting, constipation)
• Cardiovascular instability (fluctuating blood pressure, fainting)
• Poor temperature regulation
• Reduced pain and temperature sensation
• Abnormal sweating
• Sensory neuropathy
• Developmental delays

Testing is also important when there is a family history of FD, especially among people of Ashkenazi Jewish descent.

Prenatal testing is needed if both parents are known carriers.

Testing can confirm the diagnosis, guide management, and help with family planning.

IKBKAP Genetic Testing: Test Procedure and Interpretation

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

What Do Specific IKBKAP Mutations Mean?

Two pathogenic IKBKAP mutations confirm a diagnosis of FD.

FD is inherited in an autosomal recessive pattern — a child must inherit one faulty copy from each parent to be affected.

• Founder mutation: In Ashkenazi Jewish individuals, more than 99% of FD cases are caused by a common splicing mutation (IVS20+6T>C), producing a truncated, nonfunctional IKAP protein.
• Impact on Elongator function: Mutations cause a loss of proper IKAP, damaging the Elongator complex and impairing neuron development and maintenance.

Without enough functional IKAP, the nervous system cannot develop or function properly, leading to progressive autonomic and sensory problems.

What Does the Absence of Pathogenic IKBKAP Mutations Mean?

A negative IKBKAP test does not rule out all causes of autonomic or sensory neuropathies.

Other genetic conditions or non-genetic factors might explain the symptoms.

Further genetic testing and clinical evaluation may be needed if suspicion for a nerve disorder remains high.

Key Clinical Takeaways

IKBKAP encodes IKAP/ELP1, a critical protein for nerve cell development and function.

Mutations in IKBKAP cause familial dysautonomia (FD), leading to serious problems with blood pressure, digestion, pain sensation, and survival.

Genetic testing is vital for diagnosis, especially in individuals with Ashkenazi Jewish heritage.

Emerging therapies, including splicing modulators like kinetin and dietary supplements like phosphatidylserine, aim to restore IKAP levels and improve symptoms.

Understanding the role of IKBKAP highlights the importance of early detection, personalized management, and future gene therapy options for FD.

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