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Human Molecular Genetics Advance Access originally published online on July 15, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 18 2255-2267
DOI: 10.1093/hmg/ddg236
© 2003 Oxford University Press

Impaired neuronal migration and endochondral ossification in Pex7 knockout mice: a model for rhizomelic chondrodysplasia punctata

Pedro Brites1,{ddagger}, Alison M. Motley1,{ddagger},{dagger}, Pierre Gressens2, Petra A.W. Mooyer1, Ingrid Ploegaert1, Vincent Everts3, Philippe Evrard2, Peter Carmeliet4, Mieke Dewerchin4, Luc Schoonjans5, Marinus Duran1, Hans R. Waterham1, Ronald J.A. Wanders1,* and Myriam Baes6

1Academic Medical Center, Laboratory of Genetic Metabolic Diseases, Amsterdam, The Netherlands, 2INSERM E9935, Hôpital Robert-Debré, Paris, France, 3Academic Medical Center, Department of Cell Biology and Histology, Amsterdam, The Netherlands, 4Center for Transgene Technology and Gene Therapy, Flanders Institute for Biotechnology, Leuven, Belgium, 5Thromb-X, Leuven, Belgium and 6Faculty of Pharmaceutical Sciences, Katholieke Universiteit Leuven, Laboratory of Clinical Chemistry, Leuven, Belgium

Received February 27, 2003; Revised June 15, 2003; Accepted July 8, 2003

Rhizomelic chondrodysplasia punctata is a human autosomal recessive disorder characterized by skeletal, eye and brain abnormalities. The disorder is caused by mutations in the PEX7 gene, which encodes the receptor for a class of peroxisomal matrix enzymes. We describe the generation and characterization of a Pex7 mouse knockout (Pex7-/-). Pex7-/- mice are born severely hypotonic and have a growth impairment. Mortality in Pex7-/- mice is highest in the perinatal period although some Pex7-/- mice survived beyond 18 months. Biochemically Pex7-/- mice display the abnormalities related to a Pex7 deficiency, i.e. a severe depletion of plasmalogens, impaired {alpha}-oxidation of phytanic acid and impaired ß-oxidation of very-long-chain fatty acids. In the intermediate zone of the developing cerebral cortex Pex7-/- mice have an increase in neuronal density. In vivo neuronal birthdating revealed that Pex7-/- mice have a delay in neuronal migration. Analysis of bone ossification in newborn Pex7-/- mice revealed a defect in ossification of distal bone elements of the limbs as well as parts of the skull and vertebrae. These findings demonstrate that Pex7 knockout mice provide an important model to study the role of peroxisomal functioning in the pathogenesis of the human disorder.

* To whom correspondence should be addressed at: Academic Medical Center, Lab Genetic Metabolic Diseases F0-224, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands. Tel: +31 205665958; Fax: +31 206962596; Email: r.j.wanders{at}amc.uva.nl

{dagger} Present address: Cambridge Institute for Medical Research, Addenbrooke's Hospital, Clinical Biochemistry Lab5.2, Cambridge, UK

{ddagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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