title: Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation.
abstract: Rett 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.
authors.affiliation: Western Sydney Genetics Program, the Children's Hospital at Westmead, New South Wales, Australia.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Weaving
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Williamson
authors.forename: Kathie L
authors.initials: KL
authors.lastname: Friend
authors.forename: Olivia L D
authors.initials: OL
authors.lastname: McKenzie
authors.forename: Hayley
authors.initials: H
authors.lastname: Archer
authors.forename: Julie
authors.initials: J
authors.lastname: Evans
authors.forename: Angus
authors.initials: A
authors.lastname: Clarke
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Pelka
authors.forename: Patrick P L
authors.initials: PP
authors.lastname: Tam
authors.forename: Catherine
authors.initials: C
authors.lastname: Watson
authors.forename: Hooshang
authors.initials: H
authors.lastname: Lahooti
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Ellaway
authors.forename: Bruce
authors.initials: B
authors.lastname: Bennetts
authors.forename: Helen
authors.initials: H
authors.lastname: Leonard
authors.forename: Jozef
authors.initials: J
authors.lastname: Gécz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics; D004303:Dosage Compensation, Genetic; D005453:Fluorescence; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics*; D006801:Humans; D017403:In Situ Hybridization; D008607:Intellectual Disability / Q000235:genetics; D051783:Methyl-CpG-Binding Protein 2; D051379:Mice; D008822:Mice, Transgenic; D018895:Microsatellite Repeats / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics; D015518:Rett Syndrome / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D017931:DNA Primers; D004268:DNA-Binding Proteins; C497392:MECP2 protein, human; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D012097:Repressor Proteins; D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human