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.

The neurology of rhizomelic chondrodysplasia punctata

“…, but is normal in the Pex7 neo/neo mice [18][19][20][21]. Epilepsy has not been mentioned in the mice.…”

Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination

“…Decreased transcript levels of Pex7 and Agps impair ether phospholipid synthesis in Pex7 and Agps hypomorphic mice, respectively, causing partial decreases in plasmalogen levels. In these mutants, the residual levels of plasmalogens are thought to prevent the hypotonia and early lethality observed in KO mice (11,12). Nevertheless, bone, lens, and testicular defects in the hypomorphic mice mirror those of KO mice.…”

Lipidomics Analysis of Peroxisomal Disorders: Discovery of Deficits in Phosphatidyglycerol Levels in Rhizomelic Chondrodysplasia Type 1

“…To evaluate this hypothesis we investigated augmentation of cellular plasmalogens in lymphoblasts incubated with ether lipid precursors that bypass peroxisomes to augment cellular plasmalogen levels. These data suggest that ether lipid supplementation to augment plasmalogens [7,15] in RCDP1 patients also may augment phosphatidylglycerols. If this proves to be the case, then improved quality of lifestyle and longevity, relative to lung infections, may be a significant clinical benefit for RCDP children.…”

“…To further evaluate if increased catabolism of phosphatidylglycerols was potentially the result of failed attempts to restore plasmalogens via the metabolism of phosphatidylglycerols to augment diacylglycerol levels Figure 3, we investigated augmentation of plasmalogens with the ether lipid precursors, batyl alcohol and chimyl alcohol, which bypass peroxisomes in the synthesis of plasmalogens [7,15]. Chimyl alcohol was the most effective in augmenting a broad range of choline plasmalogens Figure 5, upper panel and ethanolamine plasmalogens (data not shown) in both control and RCDP1 lymphoblasts.…”