|Inhibitor of κ light polypeptide gene enhancer in B-cells, kinase complex-associated protein|
|Alt. symbols||FD, DYS, ELP1, IKAP, IKI3, TOT1, FLJ12497 and DKFZp781H1425|
|Locus||Chr. 9 q13|
IKBKAP (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein) is a human gene that provides instructions to make the IKAP protein, which is found in a variety of cells throughout the body, including brain cells. Although the exact function of the IKAP protein is not clearly understood, it probably plays a role in transcription, which is the process of making a blueprint of a gene for protein production. Researchers have identified the IKAP protein as part of a six-protein complex (called the holo-elongator complex) that interacts with enzymes necessary for transcription. The IKAP protein probably performs other functions in the cell as well, such as responding to stress. Its homolog in fly (D-elp1) has RNA-dependent RNA polymerase activity and is involved in RNA interference.
Familial dysautonomia is caused by mutations in the IKBKAP gene. Nearly all individuals with familial dysautonomia have two copies of the same mutation in each cell, which causes part of the IKBKAP gene to be skipped during transcription. (This alteration is often called exon skipping.) This skipping mutation results in a decreased amount of IKAP protein in their cells. This mutation, however, behaves inconsistently. As a result, some cells produce near normal amounts of IKAP protein, and other cells (particularly cells in the nervous system) have very little IKAP protein.
In a small number of reported familial dysautonomia cases, researchers have identified other mutations that cause a change in amino acids (the building blocks of proteins). In these cases, arginine is replaced by proline at position 696 in the IKAP protein's chain of amino acids (also written as Arg696Pro), or proline is replaced by leucine at position 914 (also written as Pro914Leu). People with one of these improper amino acid substitutions also have the skipping mutation. Together, these mutations cause the resulting IKAP protein to malfunction.
It is unclear how mutations in the IKBKAP gene lead to the signs and symptoms of familial dysautonomia. Critical activities in brain and nerve cells are probably disrupted by reduced amounts or the absence of functional IKAP protein.
|Recessive lethal study||Abnormal|
|Glucose tolerance test||Normal|
|Auditory brainstem response||Normal|
|Peripheral blood lymphocytes||Normal|
|Tail epidermis wholemount||Normal|
|All tests and analysis from|
Model organisms have been used in the study of IKBKAP function. A conditional knockout mouse line, called Ikbkaptm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out and two phenotypes were reported. No homozygous mutant embryos were identified during gestation, and in a separate study none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no significant abnormalities were observed in these animals.
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