Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/6910
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dc.contributor.authorWeaving, L.en
dc.contributor.authorChristodoulou, J.en
dc.contributor.authorWilliamson, S.en
dc.contributor.authorFriend, K.en
dc.contributor.authorMcKenzie, O.en
dc.contributor.authorArcher, H.en
dc.contributor.authorEvans, J.en
dc.contributor.authorClarke, A.en
dc.contributor.authorPelka, G.en
dc.contributor.authorTam, P.en
dc.contributor.authorWatson, C.en
dc.contributor.authorLahooti, H.en
dc.contributor.authorEllaway, C.en
dc.contributor.authorBennetts, B.en
dc.contributor.authorLeonard, H.en
dc.contributor.authorGecz, J.en
dc.date.issued2004en
dc.identifier.citationAmerican Journal of Human Genetics, 2004; 75(6):1079-1093en
dc.identifier.issn0002-9297en
dc.identifier.issn1537-6605en
dc.identifier.urihttp://hdl.handle.net/2440/6910-
dc.description.abstractRett syndrome (RTT) is a severe neurodevelopmental disorder caused, in most classic cases, by mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). A large degree of phenotypic variation has been observed in patients with RTT, both those with and without MECP2 mutations. We describe a family consisting of a proband with a phenotype that showed considerable overlap with that of RTT, her identical twin sister with autistic disorder and mild-to-moderate intellectual disability, and a brother with profound intellectual disability and seizures. No pathogenic MECP2 mutations were found in this family, and the Xq28 region that contains the MECP2 gene was not shared by the affected siblings. Three other candidate regions were identified by microsatellite mapping, including 10.3 Mb at Xp22.31-pter between Xpter and DXS1135, 19.7 Mb at Xp22.12-p22.11 between DXS1135 and DXS1214, and 16.4 Mb at Xq21.33 between DXS1196 and DXS1191. The ARX and CDKL5 genes, both of which are located within the Xp22 region, were sequenced in the affected family members, and a deletion of nucleotide 183 of the coding sequence (c.183delT) was identified in CDKL5 in the affected family members. In a screen of 44 RTT cases, a single splice-site mutation, IVS13-1G-->A, was identified in a girl with a severe phenotype overlapping RTT. In the mouse brain, Cdkl5 expression overlaps--but is not identical to--that of Mecp2, and its expression is unaffected by the loss of Mecp2. These findings confirm CDKL5 as another locus associated with epilepsy and X-linked mental retardation. These results also suggest that mutations in CDKL5 can lead to a clinical phenotype that overlaps RTT. However, it remains to be determined whether CDKL5 mutations are more prevalent in specific clinical subgroups of RTT or in other clinical presentations.en
dc.description.statementofresponsibilityWeaving, Linda S. ; Christodoulou, John ; Williamson, Sarah L. ; Friend, Kathie L. ; McKenzie, Olivia L.D. ; Archer, Hayley ; Evans, Julie ; Clarke, Angus ; Pelka, Gregory J. ; Tam, Patrick P.L. ; Watson, Catherine ; Lahooti, Hooshang ; Ellaway, Carolyn J. ; Bennetts, Bruce ; Leonard, Helen ; Gécz, Jozefen
dc.language.isoenen
dc.publisherUniv Chicago Pressen
dc.subjectBrain; Chromosomes, Human, X; Animals; Mice, Transgenic; Humans; Mice; Heredodegenerative Disorders, Nervous System; Rett Syndrome; Protein-Serine-Threonine Kinases; DNA-Binding Proteins; Chromosomal Proteins, Non-Histone; Repressor Proteins; DNA Primers; Blotting, Western; In Situ Hybridization; Pedigree; Sequence Analysis, DNA; Amino Acid Sequence; Base Sequence; Microsatellite Repeats; Haplotypes; Mutation; Fluorescence; Molecular Sequence Data; Dosage Compensation, Genetic; Methyl-CpG-Binding Protein 2; Genetic Testing; Intellectual Disabilityen
dc.titleMutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardationen
dc.typeJournal articleen
dc.identifier.rmid0020041063en
dc.identifier.doi10.1086/426462en
dc.identifier.pubid56585-
pubs.library.collectionPaediatrics publicationsen
pubs.verification-statusVerifieden
pubs.publication-statusPublisheden
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]en
Appears in Collections:Paediatrics publications

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