Comparative wide transcriptome analysis of FD and WT hESC-derived neurons together with the analysis of human brains from FD and WT 12 weeks old embryos and experimental validation of the results confirmed that synaptic vesicular and neuronal transport genes are directly or indirectly affected by IKBKAP downregulation in FD neurons.
An example of this phenomenon is observed in the neurodevelopmental disease familial dysautonomia (FD), which is caused by a single-base change in the 5' splice site (5'ss) of intron 20 in the IKBKAP gene (c.2204+6T>C).
FD is classified as a hereditary sensory and autonomic neuropathy (HSAN type III) and is both a developmental and a progressive neurodegenerative condition that results from an autosomal recessive mutation in the gene IKBKAP, also known as ELP1.
Familial dysautonomia (FD) is characterized by severe and progressive sympathetic and sensory neuron loss caused by a highly conserved germline point mutation of the human ELP1/IKBKAP gene.
HSAN type III, known as familial dysautonomia (FD), results from a single base mutation in the gene <i>IKBKAP</i> that encodes a scaffolding unit (ELP1) for a multi-subunit complex known as Elongator.
Here we demonstrated that PS treatment increases IKBAKP mRNA and IKAP protein levels in various tissues of FD mice without affecting exon 20 inclusion levels.
Mutations in IKBKAP, encoding a subunit of Elongator, cause familial dysautonomia (FD), a severe neurodevelopmental disease with complex clinical characteristics.
This new mouse model, TgFD9; Ikbkap(Δ20/flox) was created by introducing the complete human IKBKAP transgene with the major FD splice mutation (TgFD9) into a mouse that expresses extremely low levels of endogenous Ikbkap (Ikbkap(Δ20/flox)).
Finally, we identified several dysregulated miRNAs after carfilzomib treatment that target proteasome-associated mRNAs and determined that IKAP/hELP1 deficiency in FD pathology is correlated to an overactivity of the 26S proteasome.
Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia.
These findings provide insights into the mechanisms of IKBKAP exon 20 recognition, and pre-clinical proof of concept for an ASO-based targeted therapy for FD.
Baseline IKBKAP mRNA levels in white blood cells were evaluated in thirteen FD patients (fourteen crisis events) and compared to mRNA levels at the onset, during, and after recovery from the crisis.
These results provide evidence for the role of the cytosolic interactions of IKAP in cell adhesion and migration, and support the notion that cell-motility deficiencies could contribute to FD.
Familial dysautonomia (FD) is a rare children neurodegenerative disease caused due to a point mutation in the <i>IKBKAP</i> gene that results in decreased IKK complex-associated protein (IKAP) protein production.
An example of this phenomenon is observed in the neurodevelopmental disease familial dysautonomia (FD), which is caused by a single-base change in the 5' splice site (5'ss) of intron 20 in the IKBKAP gene (c.2204+6T>C).