{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The AAAS gene encodes the protein ALADIN, a member of the WD‐repeat family that is an integral component of the nuclear pore complex (NPC)."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " ALADIN normally localizes to NPCs by interacting with key membrane‐integral nucleoporins such as NDC1, ensuring its correct anchorage and thereby contributing to selective nuclear import."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "7"}]}, {"type": "t", "text": " In this role, ALADIN facilitates the nuclear import of specific proteins, including those implicated in DNA repair and oxidative stress responses. For instance, its interaction with ferritin heavy chain (FTH1) appears to enhance the nuclear translocation of FTH1, a protein that not only functions in iron storage but also in protecting the nucleus from oxidative damage."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In specialized tissues such as the adrenal cortex and neuronal cells, ALADIN’s proper NPC localization is critical for maintaining redox balance and ensuring normal steroidogenic function, as evidenced by studies showing that AAAS knockdown leads to increased oxidative stress, impaired expression of key steroidogenic enzymes, and reduced cortisol production."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}, {"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Collectively, loss-of-function mutations in AAAS disrupt ALADIN’s targeting to the NPC, compromise selective nuclear protein import, and thereby contribute to the multisystem defects observed in Triple A syndrome—an autosomal recessive disorder characterized by adrenal insufficiency, alacrima, achalasia, and neurological impairments."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Janet M Cronshaw, Michael J Matunis "}, {"type": "b", "children": [{"type": "t", "text": "The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1031047100"}], "href": "https://doi.org/10.1073/pnas.1031047100"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12730363"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12730363"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Angela Huebner, A M Kaindl, K P Knobeloch, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The triple A syndrome is due to mutations in ALADIN, a novel member of the nuclear pore complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocr Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1081/erc-200044138"}], "href": "https://doi.org/10.1081/erc-200044138"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15666842"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15666842"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Janet M Cronshaw, Andrew N Krutchinsky, Wenzhu Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Proteomic analysis of the mammalian nuclear pore complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.200206106"}], "href": "https://doi.org/10.1083/jcb.200206106"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12196509"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12196509"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Barbara Kind, Katrin Koehler, Mike Lorenz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The nuclear pore complex protein ALADIN is anchored via NDC1 but not via POM121 and GP210 in the nuclear envelope."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2009.09.080"}], "href": "https://doi.org/10.1016/j.bbrc.2009.09.080"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19782045"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19782045"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Yusuke Yamazumi, Atsushi Kamiya, Ayumu Nishida, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The transmembrane nucleoporin NDC1 is required for targeting of ALADIN to nuclear pore complexes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2009.08.096"}], "href": "https://doi.org/10.1016/j.bbrc.2009.08.096"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19703420"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19703420"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "M Krumbholz, K Koehler, A Huebner "}, {"type": "b", "children": [{"type": "t", "text": "Cellular localization of 17 natural mutant variants of ALADIN protein in triple A syndrome - shedding light on an unexpected splice mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Cell Biol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1139/o05-198"}], "href": "https://doi.org/10.1139/o05-198"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16609705"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16609705"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "H L Storr, A J L Clark, J V Priestley, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of the sites of expression of triple A syndrome mRNA in the rat using in situ hybridisation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuroscience (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neuroscience.2004.10.029"}], "href": "https://doi.org/10.1016/j.neuroscience.2004.10.029"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15680696"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15680696"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Helen L Storr, Barbara Kind, David A Parfitt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deficiency of ferritin heavy-chain nuclear import in triple a syndrome implies nuclear oxidative damage as the primary disease mechanism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Endocrinol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/me.2009-0056"}], "href": "https://doi.org/10.1210/me.2009-0056"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19855093"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19855093"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Ramona Jühlen, Jan Idkowiak, Angela E Taylor, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of ALADIN in human adrenocortical cells for oxidative stress response and steroidogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0124582"}], "href": "https://doi.org/10.1371/journal.pone.0124582"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25867024"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25867024"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "R Prasad, L A Metherell, A J Clark, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deficiency of ALADIN impairs redox homeostasis in human adrenal cells and inhibits steroidogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrinology (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/en.2013-1241"}], "href": "https://doi.org/10.1210/en.2013-1241"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23825130"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23825130"}]}]}]}