TY - JOUR
T1 - Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation
AU - Kalscheuer, Vera M.
AU - Tao, Jiong
AU - Donnelly, Andrew
AU - Hollway, Georgina
AU - Schwinger, Eberhard
AU - Kübart, Sabine
AU - Menzel, Corinna
AU - Hoeltzenbein, Maria
AU - Tommerup, Niels
AU - Eyre, Helen
AU - Harbord, Michael
AU - Haan, Eric
AU - Sutherland, Grant R.
AU - Ropers, Hans Hilger
AU - Gécz, Jozef
N1 - Funding Information:
We sincerely thank the members of the families and their clinicians, for participation in this study; C. Derwas and H. Madle, for help with cell culture; T. Fullston, for technical assistance; and B. Franco, for Xp YAC clones. This work was supported by the National Health and Medical Research Council of Australia, Deutsches Humangenom-Programm grant 01KW99087, and Nationales Genomforschungsnetzwerk grant 01GR0105.
PY - 2003/6/1
Y1 - 2003/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0038353760&partnerID=8YFLogxK
U2 - 10.1086/375538
DO - 10.1086/375538
M3 - Article
C2 - 12736870
AN - SCOPUS:0038353760
SN - 0002-9297
VL - 72
SP - 1401
EP - 1411
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -