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

Vera M. Kalscheuer, Jiong Tao, Andrew Donnelly, Georgina Hollway, Eberhard Schwinger, Sabine Kübart, Corinna Menzel, Maria Hoeltzenbein, Niels Tommerup, Helen Eyre, Michael Harbord, Eric Haan, Grant R. Sutherland, Hans Hilger Ropers, Jozef Gécz

Research output: Contribution to journalArticlepeer-review

224 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1401-1411
Number of pages11
JournalAmerican Journal of Human Genetics
Volume72
Issue number6
DOIs
Publication statusPublished - 1 Jun 2003
Externally publishedYes

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