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dc.contributor.authorEfthymiou, Stephanie
dc.contributor.authorScala, Marcello
dc.contributor.authorNagaraj, Vini
dc.contributor.authorOchenkowska, Katarzyna
dc.contributor.authorKomdeur, Fenne L
dc.contributor.authorLiang, Robin Amanda
dc.contributor.authorAbdel-Hamid, Mohamed S
dc.contributor.authorSultan, Tipu
dc.contributor.authorBarøy, Tuva
dc.contributor.authorVan Ghelue, Marijke
dc.contributor.authorVona, Barbara
dc.contributor.authorMaroofian, Reza
dc.contributor.authorZafar, Faisal
dc.contributor.authorAlkuraya, Fowzan S
dc.contributor.authorZaki, Maha S
dc.contributor.authorSeverino, Mariasavina
dc.contributor.authorDuru, Kingsley C
dc.contributor.authorTryon, Robert C
dc.contributor.authorBrauteset, Lin
dc.contributor.authorAnsari, Morad
dc.contributor.authorHamilton, Mark
dc.contributor.authorVan Haelst, Mieke M
dc.contributor.authorVan Haaften, Gijs
dc.contributor.authorZara, Federico
dc.contributor.authorHoulden, Henry
dc.contributor.authorSamarut, Éric
dc.contributor.authorNichols, Colin G
dc.contributor.authorSmeland, Marie Louise Falkenberg
dc.contributor.authorMcClenaghan, Conor
dc.date.accessioned2024-08-29T11:56:49Z
dc.date.available2024-08-29T11:56:49Z
dc.date.issued2024-01-13
dc.description.abstractLoss-of-function mutation of ABCC9, the gene encoding the SUR2 subunit of ATP sensitive-potassium (KATP) channels, was recently associated with autosomal recessive ABCC9-related intellectual disability and myopathy syndrome (AIMS). Here we identify nine additional subjects, from seven unrelated families, harbouring different homozygous loss-of-function variants in ABCC9 and presenting with a conserved range of clinical features.<p> <p>All variants are predicted to result in severe truncations or in-frame deletions within SUR2, leading to the generation of non-functional SUR2-dependent KATP channels. Affected individuals show psychomotor delay and intellectual disability of variable severity, microcephaly, corpus callosum and white matter abnormalities, seizures, spasticity, short stature, muscle fatigability and weakness. Heterozygous parents do not show any conserved clinical pathology but report multiple incidences of intra-uterine fetal death, which were also observed in an eighth family included in this study. In vivo studies of abcc9 loss-of-function in zebrafish revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility.<p> <p>Our findings define an ABCC9 loss-of-function-related phenotype, expanding the genotypic and phenotypic spectrum of AIMS and reveal novel human pathologies arising from KATP channel dysfunction.en_US
dc.identifier.citationEfthymiou, Scala, Nagaraj, Ochenkowska, Komdeur, Liang, Abdel-Hamid, Sultan, Barøy, Van Ghelue, Vona, Maroofian, Zafar, Alkuraya, Zaki, Severino, Duru, Tryon, Brauteset, Ansari, Hamilton, Van Haelst, Van Haaften, Zara, Houlden, Samarut, Nichols, Smeland, McClenaghan. Novel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndrome. Brain. 2024;147(5):1822-1836
dc.identifier.cristinIDFRIDAID 2271691
dc.identifier.doi10.1093/brain/awae010
dc.identifier.issn0006-8950
dc.identifier.issn1460-2156
dc.identifier.urihttps://hdl.handle.net/10037/34475
dc.language.isoengen_US
dc.publisherOxford University Pressen_US
dc.relation.journalBrain
dc.rights.holderCopyright 2024 The Author(s)en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0en_US
dc.rightsAttribution 4.0 International (CC BY 4.0)en_US
dc.titleNovel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndromeen_US
dc.type.versionpublishedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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Attribution 4.0 International (CC BY 4.0)
Med mindre det står noe annet, er denne innførselens lisens beskrevet som Attribution 4.0 International (CC BY 4.0)