Ген IKBKAP: структура, функции и роль в нейроразвитии.

Human gene encoding the IKAP protein

IKBKAP (inhibitor of kappa light polypeptide gene enhancer in B cells, kinase complex associated protein) is a human gene encoding the IKAP protein, which is ubiquitously expressed at varying levels in all tissue types, including brain cells. which allows for transcriptional elongation by RNA polymerase II. Further evidence has implicated the IKAP protein as being critical in neuronal development, and directs that decreased expression of IKAP in certain cell types is the molecular basis for the severe, neurodevelopmental disorder familial dysautonomia. Other pathways that have been connected to IKAP protein function in a variety of organisms include tRNA modification, cell motility, Ikbkap in mice, and D elp1 in fruit flies. The fruit fly homolog (D elp1) has RNA dependent RNA polymerase activity and is involved in RNA interference. The IKBKAP gene is located on the long (q) arm of chromosome 9 at position 31, from base pair 108,709,355 to base pair 108,775,950.

Originally, it was proposed that the IKBKAP gene in humans was encoding a scaffolding protein (IKAP) for the IκB enzyme kinase (IKK) complex, which is involved in pro inflammatory cytokine signal transduction in the NF κB signalling pathway. However, this was subsequently disproven when researchers applied a gel filtration method and could not identify IKK complexes contained in fractions with IKAP, thus dissociating IKAP from having a role in the NF κB signalling pathway. Later, it was discovered that IKAP functions as a cytoplasmic scaffold protein in the mammalian JNK signalling pathway which is activated in response to stress stimuli. In an in vivo experiment, researchers showed direct interaction between IKAP and JNK induced by the application of stressors such as ultraviolet light and TNF α (a pro inflammatory cytokine). IKAP is now also widely acknowledged to have a role in transcriptional elongation in humans. The RNA polymerase II holoenzyme constitutes partly of a multi subunit histone acetyltransferase element known as the RNA polymerase II elongator complex, of which IKAP is one subunit. The association of the elongator complex with RNA polymerase II holoenzyme is necessary for subsequent binding to nascent pre mRNA of certain target genes, and thus their successful transcription. Specifically, within the cell, the depletion of functional elongater complexes due to low IKAP expression has been found to have a profound effect on transcription of genes involved in cell migration. In yeast, experimental data shows the elongator complex functioning in a variety of processes — from exocytosis to tRNA modification. This finding demonstrates that the function of the elongator complex is not conserved among species.

Familial dysautonomia (also known as “Riley Day syndrome”) is a complex congenital neurodevelopmental disease, characterized by unusually low numbers of neurons in the sensory and autonomic nervous systems. The resulting symptoms of patients include gastrointestinal dysfunction, scoliosis, and pain insensitivity. This disease is especially prevalent in the Ashkenazi Jewish population, where 1/3600 live births present familial dysautonomia. 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). Together, these mutations cause the resulting IKAP protein to malfunction. As an autosomal recessive disorder, two mutated alleles of the IKBKAP gene are required for the disorder to manifest. However, despite the predominance of the same single base mutation being the reputed cause of familial dysautonomia, the severity of the affected phenotype varies within and between families.