TY - JOUR
T1 - A Pex7 hypomorphic mouse model for plasmalogen deficiency affecting the lens and skeleton
AU - Braverman, Nancy
AU - Zhang, Rui
AU - Chen, Li
AU - Nimmo, Graeme
AU - Scheper, Sarah
AU - Tran, Tammy
AU - Chaudhury, Rupsa
AU - Moser, Ann
AU - Steinberg, Steven
N1 - Funding Information:
This project was funded by an NIH R01HD39747 from the NICHD to Johns Hopkins University (N.B.). We also acknowledge the support of the Nicholas Davis Duke Memorial Endowment Fund at the Johns Hopkins Dept. of Pediatrics, Dr. Cory Brayton, Director of the Phenotyping Core at Johns Hopkins for review of the histopathology, Drs. Debasish Sinha and Sam Zigler, of the Wilmer Eye Institute, Johns Hopkins, for review of the lens histology.
PY - 2010/4
Y1 - 2010/4
N2 - 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.
AB - 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.
KW - Mouse models
KW - Peroxisome biogenesis disorder
KW - Pex7
KW - Phytanic acid
KW - Plasmalogens
KW - Rhizomelic chondrodysplasia punctata
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U2 - 10.1016/j.ymgme.2009.12.005
DO - 10.1016/j.ymgme.2009.12.005
M3 - Article
C2 - 20060764
AN - SCOPUS:77649341208
SN - 1096-7192
VL - 99
SP - 408
EP - 416
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 4
ER -