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.
Kalscheuer
Vera M
VM
Max-Planck-Institute for Molecular Genetics, Berlin, Germany. kalscheu@molgen.mpg.de
Tao
Jiong
J
Donnelly
Andrew
A
Hollway
Georgina
G
Schwinger
Eberhard
E
Kübart
Sabine
S
Menzel
Corinna
C
Hoeltzenbein
Maria
M
Tommerup
Niels
N
Eyre
Helen
H
Harbord
Michael
M
Haan
Eric
E
Sutherland
Grant R
GR
Ropers
Hans-Hilger
HH
Gécz
Jozef
J
D001483:Base Sequence; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7; D002658:Developmental Disabilities / Q000235:genetics; D004303:Dosage Compensation, Genetic; D005260:Female; D005801:Genes, Homeobox; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics*; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D013036:Spasms, Infantile / Q000235:genetics*; D014178:Translocation, Genetic
D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human