Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation

Am J Hum Genet. 2004 Dec;75(6):1149-54. doi: 10.1086/426460.

Abstract

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.

Publication types

  • Case Reports
  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Chromatography, High Pressure Liquid
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomes, Human, X / genetics*
  • DNA-Binding Proteins / genetics
  • Heredodegenerative Disorders, Nervous System / genetics*
  • Humans
  • Infant
  • Methyl-CpG-Binding Protein 2
  • Molecular Sequence Data
  • Mutation, Missense / genetics*
  • Pedigree
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / physiology
  • Repressor Proteins / genetics
  • Sequence Alignment
  • Spasms, Infantile / genetics*

Substances

  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • MECP2 protein, human
  • Methyl-CpG-Binding Protein 2
  • Repressor Proteins
  • Protein-Serine-Threonine Kinases
  • CDKL5 protein, human

Associated data

  • GENBANK/AAD28798
  • GENBANK/AL109798
  • GENBANK/Z92542
  • RefSeq/NM_003159
  • RefSeq/NP_003150
  • RefSeq/NP_003939
  • RefSeq/NP_004187
  • RefSeq/NP_057592
  • RefSeq/XP_356367