Impaired neuronal migration and endochondral ossification in Pex7 knockout mice: a model for rhizomelic chondrodysplasia punctata.
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 beta-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.
Brites
Pedro
P
Academic Medical Center, Laboratory of Genetic Metabolic Diseases F0-224, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
Motley
Alison M
AM
Gressens
Pierre
P
Mooyer
Petra A W
PA
Ploegaert
Ingrid
I
Everts
Vincent
V
Evrard
Philippe
P
Carmeliet
Peter
P
Dewerchin
Mieke
M
Schoonjans
Luc
L
Duran
Marinus
M
Waterham
Hans R
HR
Wanders
Ronald J A
RJ
Baes
Myriam
M
D000101:Acetyl-CoA C-Acetyltransferase / Q000096:biosynthesis; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000201:enzymology; D002465:Cell Movement; D002478:Cells, Cultured; D018902:Chondrodysplasia Punctata, Rhizomelic / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004032:Diet; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D018390:Gene Targeting; D008099:Liver / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D010006:Osteoblasts / Q000648:ultrastructure; D010010:Osteoclasts / Q000648:ultrastructure; D010012:Osteogenesis; D010084:Oxidation-Reduction; D000074437:Peroxisomal Targeting Signal 2 Receptor; D020675:Peroxisomes / Q000378:metabolism; D010831:Phytanic Acid / Q000378:metabolism; D010836:Phytol / Q000378:metabolism; D010955:Plasmalogens / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics*; D013997:Time Factors
C000614269:PEX7 protein, human; D000074437:Peroxisomal Targeting Signal 2 Receptor; D010955:Plasmalogens; D018160:Receptors, Cytoplasmic and Nuclear; D010831:Phytanic Acid; D010836:Phytol; D000101:Acetyl-CoA C-Acetyltransferase