TY - JOUR
T1 - Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation
AU - Weaving, Linda S.
AU - Christodoulou, John
AU - Williamson, Sarah L.
AU - Friend, Kathie L.
AU - McKenzie, Olivia L.D.
AU - Archer, Hayley
AU - Evans, Julie
AU - Clarke, Angus
AU - Pelka, Gregory J.
AU - Tam, Patrick P.L.
AU - Watson, Catherine
AU - Lahooti, Hooshang
AU - Ellaway, Carolyn J.
AU - Bennetts, Bruce
AU - Leonard, Helen
AU - Gécz, Jozef
N1 - Funding Information:
We would like to thank the families involved in this study, for their invaluable contribution. We are grateful to Laurent Villard (INSERM U491, Faculté de Medecine La Timone, Marseille, France) for providing us with DNA samples, from a number of patients with RTT, for CDKL5 mutation screening. We would also like to acknowledge the help of Joanna Crawford with X-inactivation studies and the technical support of Sara Lonergan, Julianne Jackson, Zhanhe Wu, and Rose White. We would also like to thank Dr. Alison Kerr for her clinical opinion and helpful comments. Financial support for this research was provided by the Rett Syndrome Association of NSW, the Rett Syndrome Australian Research Fund, the National Health and Medical Research Council of Australia (NHMRC), and the Country Women’s Association of NSW. The U.K. laboratory research was performed with grant support from The Health Foundation. G.J.P. is an NHMRC Dora Lush Biomedical Scholar, J.G. is an NHMRC Senior Research Fellow, and P.P.L.T. is an NHMRC Senior Principal Research Fellow.
PY - 2004/12
Y1 - 2004/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=8844269073&partnerID=8YFLogxK
U2 - 10.1086/426462
DO - 10.1086/426462
M3 - Article
C2 - 15492925
AN - SCOPUS:8844269073
VL - 75
SP - 1079
EP - 1093
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 6
ER -