A Pex7 hypomorphic mouse model for plasmalogen deficiency affecting the lens and skeleton
Open accessAbstract
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.
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Hypomorphic mouse models with residual Pex7 or Agps transcript and residual ether lipids mimic milder human RCDP.
“Furthermore, hypomorphic mouse models with residual transcript levels of the Pex7 [215] or the Agps [216] gene and, consequently, residual levels of ether lipids have been described, which mimic the milder form of the human disease.”
From Peroxisomes in brain development and function (2016) · cites this paper as [215]
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Peroxisomes in brain development and function
Berger, J., Dorninger, F., Forss-Petter, S., & Kunze, M. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.12.005 · Cited by 194 · see citing works
“However, neuroinflammation with marked microglia activationwas observed upon combined deficiency of Pex7 and Abcd1 in 11-months-old mice of mixed background (Swiss Webster and C57BL/ 6J:129S1) [220] suggesting that ether lipid deficiency has little effect on immune cell activation under basal conditions but more drast…”
BackgroundInfluentialPeroxisome-mediated metabolism is required for immune response to microbial infection
Di Cara, F., Sheshachalam, A., Braverman, N. E., Rachubinski, R. A., & Simmonds, A. J. (2017) · Immunity · doi:10.1016/j.immuni.2017.06.016 · Cited by 155 · see citing works
Self-citationBarøy, T., Koster, J., Strømme, P., Ebberink, M. S., Misceo, D., Ferdinandusse, S., Holmgren, A., Hughes, T., Merckoll, E., Westvik, J., et al. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv305 · Cited by 81 · see citing works
The neurology of rhizomelic chondrodysplasia punctata
Bams-Mengerink, A. M., Koelman, J. H., Waterham, H., Barth, P. G., & Poll-The, B. T. (2013) · Orphanet Journal of Rare Diseases · doi:10.1186/1750-1172-8-174 · Cited by 59 · see citing works
- Authors
- Braverman, N., Zhang, R., Chen, L., Nimmo, G., Scheper, S., Tran, T., Chaudhury, R., Moser, A., & Steinberg, S.
- Affiliations
- Montreal Children's Hospital (CA)
- Johns Hopkins University (US)
- Kennedy Krieger Institute (US)
- Corresponding author
- Braverman, Nancy
- Venue
- Molecular Genetics and Metabolism
- Publisher
- Elsevier BV
- Published
- 2010-04
- Volume
- 99
- Issue
- 4
- Pages
- 408-416
- ISSN
- 1096-7192 (ISSN-L)
- PMC
- PMC2839039
- OpenAlex
- W2042023245
- Cited by
- 66
- References
- 52
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 5 · 2020: 2 · 2019: 4 · 2018: 1 · 2017: 7 · 2016: 2 · 2015: 7 · 2014: 8 · 2013: 5 · 2012: 5
- FWCI
- 2.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Genetics and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Duke Endowment
- Johns Hopkins University
- National Institutes of Health
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD39747, R01HD039747)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- PEX7, peroxisome biogenesis disorders, congenital cataract, endochondral ossification, phytanic acid accumulation, plasmalogen biosynthesis, ether phospholipids, skeletal abnormalities
- MeSH terms
- Peroxisomal Targeting Signal 2 Receptor, Animals, Bone and Bones, Cells, Cultured, Disease Models, Animal, Glyceryl Ethers, Lens, Crystalline, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Phytanic Acid, Plasmalogens, Tissue Distribution, Receptors, Cytoplasmic and Nuclear, Chondrodysplasia Punctata, Rhizomelic, Dietary Supplements, Peroxisomes, Mice
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