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Type: Journal article
Title: Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation
Author: Weaving, L.
Christodoulou, J.
Williamson, S.
Friend, K.
McKenzie, O.
Archer, H.
Evans, J.
Clarke, A.
Pelka, G.
Tam, P.
Watson, C.
Lahooti, H.
Ellaway, C.
Bennetts, B.
Leonard, H.
Gecz, J.
Citation: American Journal of Human Genetics, 2004; 75(6):1079-1093
Publisher: Univ Chicago Press
Issue Date: 2004
ISSN: 0002-9297
1537-6605
Statement of
Responsibility: 
Weaving, 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, Jozef
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.
Keywords: Brain
Chromosomes, Human, X
Animals
Mice, Transgenic
Humans
Mice
Heredodegenerative Disorders, Nervous System
Rett Syndrome
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 Disability
Protein Serine-Threonine Kinases
DOI: 10.1086/426462
Appears in Collections:Aurora harvest 5
Paediatrics publications

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