Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation.
Recently, we showed that truncation of the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene caused mental retardation and severe neurological symptoms in two female patients. Here, we report that de novo missense mutations in CDKL5 are associated with a severe phenotype of early-onset infantile spasms and clinical features that overlap those of other neurodevelopmental disorders, such as Rett syndrome and Angelman syndrome. The mutations are located within the protein kinase domain and affect highly conserved amino acids; this strongly suggests that impaired CDKL5 catalytic activity plays an important role in the pathogenesis of this neurodevelopmental disorder. In view of the overlapping phenotypic spectrum of CDKL5 and MECP2 mutations, it is tempting to speculate that these two genes play a role in a common pathogenic process.
Tao
Jiong
J
Max-Planck-Institute for Molecular Genetics, Berlin, Germany.
Van Esch
Hilde
H
Hagedorn-Greiwe
M
M
Hoffmann
Kirsten
K
Moser
Bettina
B
Raynaud
Martine
M
Sperner
Jürgen
J
Fryns
Jean-Pierre
JP
Schwinger
Eberhard
E
Gécz
Jozef
J
Ropers
Hans-Hilger
HH
Kalscheuer
Vera M
VM
D000595:Amino Acid Sequence; D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics*; D006801:Humans; D007223:Infant; D051783:Methyl-CpG-Binding Protein 2; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics; D016415:Sequence Alignment; D013036:Spasms, Infantile / Q000235:genetics*
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D012097:Repressor Proteins; D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human