Metabolomic Profiling Reveals Brain Lipid Alterations in PEX7-Deficient Models of Rhizomelic Chondrodysplasia Punctata

Authors

• Riya Sankhe
• Meredith I Williams
• Wedad Fallatah
• Laura Mackay
• Mary Layne Brown
• Pranjali Bhagwat
• Sarah H Elsea
• Nancy Braverman
• Michael F Wangler

Language

English

Publication Date

12-19-2025

Journal

Biomolecules

DOI

10.3390/biom16010006

PMID

41594547

PMCID

PMC12839017

PubMedCentral® Posted Date

12-19-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Rhizomelic chondrodysplasia punctata type 1 (RCDP1) is a peroxisomal disorder characterized by skeletal shortening, intellectual disability, seizures, cataracts, and reduced lifespans. RCDP1 is caused by biallelic loss-of-function variants in PEX7, which encodes a protein required for importing select enzymes into the peroxisome matrix, including those essential for ether lipid synthesis (e.g., plasmalogens) and the branched-chain fatty acid catabolism. Plasmalogen deficiency is a hallmark of RCDP1 and other peroxisomal disorders, including RCDP types 2-5 (RCDP2-5) and Zellweger spectrum disorders (ZSD). Here, we performed comprehensive metabolomic profiling of clinical samples from RCDP patients and Pex7-deficient mouse models. We identified profound neurometabolic disturbances in the cerebral cortex and cerebellum of Pex7-deficient mice involving multiple lipid classes, including phosphatidylethanolamines (PEs), phosphatidylcholines (PCs), acylcarnitines, and sphingomyelins. Notably, many of these neurometabolic alterations were absent in patient and Pex7-deficient mouse plasma, indicating that plasma-based profiling can underrepresent the extent of CNS lipid remodeling. Overall, these findings reveal novel insights into neurometabolic adaptations to plasmalogen deficiency and suggest the potential involvement of additional pathways that may contribute to neurological dysfunction in RCDP.

Keywords

Chondrodysplasia Punctata, Rhizomelic, Animals, Mice, Humans, Disease Models, Animal, Brain, Peroxisome-Targeting Signal 1 Receptor, Metabolomics, Lipid Metabolism, Mice, Knockout, Male, Plasmalogens, Female, Peroxisomal Targeting Signal 2 Receptor, peroxisome, Pex7, metabolomics, mouse models, peroxisome biogenesis disorders, plasmalogen, ether lipids

Published Open-Access

yes

Recommended Citation

Sankhe, Riya; Williams, Meredith I; Fallatah, Wedad; et al., "Metabolomic Profiling Reveals Brain Lipid Alterations in PEX7-Deficient Models of Rhizomelic Chondrodysplasia Punctata" (2025). Duncan NRI Faculty and Staff Publications. 228.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/228