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Human Molecular Genetics, 2000, Vol. 9, No. 2 227-236
© 2000 Oxford University Press

A mouse model for valproate teratogenicity: parental effects, homeotic transformations, and altered HOX expression

Antonio Faiella+, Marius Wernig2,+, G. Giacomo Consalez1, Ute Hostick2, Clementine Hofmann2, Elisabeth Hustert2, Edoardo Boncinelli1, Rudi Balling2 and Joseph H. Nadeau3

DIBIT and 1Department of Neuroscience, San Raffaele Scientific Institute, Milan, Italy, 2Institut für Säugetiergenetik, GSF-Forschungszentrum für Umwelt und Gesundheit, D-85758, Neuherberg, Germany, 3Department of Genetics, Case Western Reserve University School of Medicine and Center for Human Genetics, University Hospitals of Cleveland, Cleveland, OH 44106, USA

Valproate (VPA) is one of several effective anti-epileptic and mood-stabilizing drugs, many of which are also potent teratogens in humans and several other mammalian species. Variable teratogenicity among inbred strains of laboratory mice suggests that genetic factors influence susceptibility. While studying the genetic basis for VPA teratogenicity in mice, we discovered that parental factors influence fetal susceptibility to induced malformations. Detailed examination of these malformations revealed that many were homeotic transformations. To test whether VPA, like retinoic acid (RA), alters HOX expression, pluripotent human embryonal carcinoma cells were treated with VPA or RA and Hox expression assessed. Altered expression of specific Hox genes may thus account for the homeotic transformations and other malformations found in VPA-treated fetuses.

+ These authors contributed equally to this work

§ To whom correspondence should be addressed at: Department of Genetics, BRB-630, CWRU, 10900 Euclid Avenue, Cleveland, OH 44106, USA. Tel: +1 216 368 0581; Fax: +1 216 368 3432; Email: jhn4@po.cwru.edu


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