Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation.

X-linked West syndrome, also called "X-linked infantile spasms" (ISSX), is characterized by early-onset generalized seizures, hypsarrhythmia, and mental retardation. Recently, we have shown that the majority of the X-linked families with infantile spasms carry mutations in the aristaless-related homeobox gene (ARX), which maps to the Xp21.3-p22.1 interval, and that the clinical picture in these patients can vary from mild mental retardation to severe ISSX with additional neurological abnormalities. Here, we report a study of two severely affected female patients with apparently de novo balanced X;autosome translocations, both disrupting the serine-threonine kinase 9 (STK9) gene, which maps distal to ARX in the Xp22.3 region. We show that STK9 is subject to X-inactivation in normal female somatic cells and is functionally absent in the two patients, because of preferential inactivation of the normal X. Disruption of the same gene in two unrelated patients who have identical phenotypes (consisting of early-onset severe infantile spasms, profound global developmental arrest, hypsarrhythmia, and severe mental retardation) strongly suggests that lack of functional STK9 protein causes severe ISSX and that STK9 is a second X-chromosomal locus for this disorder.

[1]  B. Dutrillaux,et al.  High resolution R- and G-banding on the same preparation , 2004, Human Genetics.

[2]  W. Dobyns,et al.  Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans , 2002, Nature Genetics.

[3]  I. Scheffer,et al.  X-linked myoclonic epilepsy with spasticity and intellectual disability: Mutation in the homeobox gene ARX , 2002, Neurology.

[4]  I. Scheffer,et al.  Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX , 2002, Brain and Development.

[5]  J. Fryns,et al.  ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation. , 2002, Human molecular genetics.

[6]  I. Scheffer,et al.  Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy , 2002, Nature Genetics.

[7]  R. Borgatti,et al.  Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome. , 2001, American journal of human genetics.

[8]  A. Rosenthal,et al.  Molecular cloning of Xp11 breakpoints in two unrelated mentally retarded females with X;autosome translocations , 2000, Cytogenetic and Genome Research.

[9]  T. Rosenberg,et al.  Characterization of two unusual RS1 gene deletions segregating in Danish retinoschisis families , 2000, Human mutation.

[10]  Richard F. Thompson,et al.  Identification of Variants and Dual Promoters of Murine Serine/Threonine Kinase KKIAMRE , 2000, Journal of neurochemistry.

[11]  Richard F. Thompson,et al.  Learning Induces a CDC2-Related Protein Kinase, KKIAMRE , 1999, The Journal of Neuroscience.

[12]  S. Lenzner,et al.  Genomic structure and comparative analysis of nine Fugu genes: conservation of synteny with human chromosome Xp22.2-p22.1. , 1999, Genome research.

[13]  S. Claes,et al.  X linked mental retardation and infantile spasms in a family: new clinical data and linkage to Xp11.4-Xp22.11 , 1999, Journal of medical genetics.

[14]  N. Tommerup,et al.  Systematic characterisation of disease associated balanced chromosome rearrangements by FISH: cytogenetically and genetically anchored YACs identify microdeletions and candidate regions for mental retardation genes , 1999, Journal of medical genetics.

[15]  S. Langlois,et al.  Confirmation of linkage in X‐linked infantile spasms (West syndrome) and refinement of the disease locus to Xp21.3‐Xp22.1 , 1999, Clinical genetics.

[16]  A. Ballabio,et al.  Identification and characterization of a novel serine-threonine kinase gene from the Xp22 region. , 1998, Genomics.

[17]  M. Gessler,et al.  Transcript map of a 900-kb genomic region in Xp22.1-p22.2: identification of 12 novel genes. , 1998, Genomics.

[18]  L. Lagae,et al.  The X‐linked infantile spasms syndrome (Mim 308350) maps to Xp 11.4–Xpter in two pedigrees , 1997, Annals of neurology.

[19]  J. Gécz,et al.  Gene structure and subcellular localization of FMR2, a member of a new family of putative transcription activators. , 1997, Genomics.

[20]  R. Davis,et al.  Molecular cloning of the epidermal growth factor-stimulated protein kinase p56 KKIAMRE. , 1996, Oncogene.

[21]  D. Dickson,et al.  The Distribution and Biochemical Properties of a Cdc2‐Related Kinase, KKIALRE, in Normal and Alzheimer Brains , 1995, Journal of neurochemistry.

[22]  S. Lukyanov,et al.  An improved PCR method for walking in uncloned genomic DNA. , 1995, Nucleic acids research.

[23]  U. Francke,et al.  Common sequence motifs at the rearrangement sites of a constitutional X/autosome translocation and associated deletion. , 1992, American journal of human genetics.

[24]  M. Nieto Barrera.  [Infantile spasms]. , 1990, Anales espanoles de pediatria.