{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ELP1 (also known as IKAP), a core subunit of the multi‐protein Elongator complex, plays an essential dual role in regulating both gene expression and cytoskeletal dynamics. In the nucleus, ELP1 is required for efficient transcriptional elongation and proper histone acetylation, as well as for the catalytic modification of tRNA wobble uridines. In familial dysautonomia (FD), a mutation in the IKBKAP gene leads to tissue‐specific skipping of exon 20 and a consequent reduction in ELP1 protein levels. This insufficiency impairs transcription of key target genes—many of which are involved in cell motility—and disrupts tRNA modification, ultimately compromising protein translation fidelity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, studies using animal models have demonstrated that loss of ELP1 function in neural crest–derived and post‐migratory neurons results in defective neurite outgrowth, abnormal cytoskeletal organization, and failed target innervation. These defects contribute to the progressive degeneration of sensory and autonomic neurons and, in severe cases, lead to embryonic lethality due to impaired neurovascular development and defective meiotic processes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Furthermore, alterations in cytoskeletal regulators such as filamin A and SCG10, observed in cells with reduced ELP1, indicate that the protein also has important non‐nuclear functions. These include maintaining proper cell adhesion, migration, and neurite extension, all of which are critical for nervous system development and maintenance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore that ELP1 is indispensable for both nuclear processes—ensuring accurate transcriptional output and tRNA modifications—and cytoplasmic pathways that regulate the cytoskeleton. Any perturbation in ELP1 levels, as seen in FD and related disorders, therefore disrupts a critical network of gene expression and structural regulation, leading to severe neurodevelopmental and neurodegenerative consequences."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Pierre Close, Nicola Hawkes, Isabelle Cornez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcription impairment and cell migration defects in elongator-depleted cells: implication for familial dysautonomia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2006.04.017"}], "href": "https://doi.org/10.1016/j.molcel.2006.04.017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16713582"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16713582"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Math P Cuajungco, Maire Leyne, James Mull, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tissue-specific reduction in splicing efficiency of IKBKAP due to the major mutation associated with familial dysautonomia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/368263"}], "href": "https://doi.org/10.1086/368263"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12577200"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12577200"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yei-Tsung Chen, Matthew M Hims, Ranjit S Shetty, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of mouse Ikbkap, a subunit of elongator, leads to transcriptional deficits and embryonic lethality that can be rescued by human IKBKAP."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.01313-08"}], "href": "https://doi.org/10.1128/MCB.01313-08"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19015235"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19015235"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Lars Dan Johansen, Tiina Naumanen, Astrid Knudsen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IKAP localizes to membrane ruffles with filamin A and regulates actin cytoskeleton organization and cell migration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.013722"}], "href": "https://doi.org/10.1242/jcs.013722"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18303054"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18303054"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Fu-Jung Lin, Li Shen, Chuan-Wei Jang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ikbkap/Elp1 deficiency causes male infertility by disrupting meiotic progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1003516"}], "href": "https://doi.org/10.1371/journal.pgen.1003516"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23717213"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23717213"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "David Cheishvili, Channa Maayan, Rachel Cohen-Kupiec, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IKAP/Elp1 involvement in cytoskeleton regulation and implication for familial dysautonomia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddr036"}], "href": "https://doi.org/10.1093/hmg/ddr036"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21273291"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21273291"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "David Cheishvili, Channa Maayan, Yoav Smith, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IKAP/hELP1 deficiency in the cerebrum of familial dysautonomia patients results in down regulation of genes involved in oligodendrocyte differentiation and in myelination."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddm157"}], "href": "https://doi.org/10.1093/hmg/ddm157"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17591626"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17591626"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Paula Dietrich, Shanta Alli, Revathi Shanmugasundaram, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IKAP expression levels modulate disease severity in a mouse model of familial dysautonomia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/dds354"}], "href": "https://doi.org/10.1093/hmg/dds354"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22922231"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22922231"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Hadas Keren, Maya Donyo, David Zeevi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phosphatidylserine increases IKBKAP levels in familial dysautonomia cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0015884"}], "href": "https://doi.org/10.1371/journal.pone.0015884"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21209961"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21209961"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Matthew M Hims, Ranjit S Shetty, James Pickel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A humanized IKBKAP transgenic mouse models a tissue-specific human splicing defect."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genomics (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ygeno.2007.05.012"}], "href": "https://doi.org/10.1016/j.ygeno.2007.05.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17644305"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17644305"}]}]}]}