title: A Pex7 hypomorphic mouse model for plasmalogen deficiency affecting the lens and skeleton.
abstract: Rhizomelic chondrodysplasia punctata type 1 is a peroxisome biogenesis disorder with the clinical features of rhizomelia, abnormal epiphyseal calcifications, congenital cataracts, and profound growth and developmental delays. It is a rare autosomal recessive disorder, caused by defects in the peroxisome receptor, PEX7. The pathology results from a deficiency of plasmalogens, a critical class of ether phospholipids whose functions are largely unknown. To study plasmalogens in an animal model, avoid early mortality and facilitate therapeutic investigations in this disease, we engineered a hypomorphic mouse model in which Pex7 transcript levels are reduced to less than 5% of wild type. These mice are born in expected ratios, are fertile and have a normal life span. However, they are petite and develop early cataracts. Further investigations showed delayed endochondral ossification and abnormalities in lens fibers. The biochemical features of reduced Pex7 function were reproduced in this model, including tissue plasmalogen deficiency, phytanic acid accumulation, reduced import of Pex7 ligands and consequent defects in plasmalogen biosynthesis and phytanic acid oxidation. Dietary supplementation with batyl alcohol, a plasmalogen precursor, recovered ether phospholipids in blood, but did not alter the clinical phenotype. The relatively mild phenotype of these mice mimics patients with milder PEX7 defects, and highlights the skeleton and lens as sensitive markers of plasmalogen deficiency. The role of plasmalogens in the normal function of these tissues at various ages can now be studied and additional therapeutic interventions tested in this model.
authors.affiliation: Department of Human Genetics and Pediatrics, Montreal Children's Hospital Research Institute, McGill University, Montreal, QC, Canada. nancy.braverman@mcgill.ca
authors.forename: Nancy
authors.initials: N
authors.lastname: Braverman
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Graeme
authors.initials: G
authors.lastname: Nimmo
authors.forename: Sarah
authors.initials: S
authors.lastname: Scheper
authors.forename: Tammy
authors.initials: T
authors.lastname: Tran
authors.forename: Rupsa
authors.initials: R
authors.lastname: Chaudhury
authors.forename: Ann
authors.initials: A
authors.lastname: Moser
authors.forename: Steven
authors.initials: S
authors.lastname: Steinberg
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism*; D002478:Cells, Cultured; D018902:Chondrodysplasia Punctata, Rhizomelic / Q000235:genetics* / Q000628:therapy; D019587:Dietary Supplements; D004195:Disease Models, Animal; D005995:Glyceryl Ethers / Q000627:therapeutic use; D007908:Lens, Crystalline / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000074437:Peroxisomal Targeting Signal 2 Receptor; D020675:Peroxisomes / Q000502:physiology*; D010641:Phenotype; D010831:Phytanic Acid / Q000378:metabolism; D010955:Plasmalogens / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency*; D014018:Tissue Distribution
chemical_list: D005995:Glyceryl Ethers; D000074437:Peroxisomal Targeting Signal 2 Receptor; D010955:Plasmalogens; D018160:Receptors, Cytoplasmic and Nuclear; D010831:Phytanic Acid; C033433:batyl alcohol