Abstract
Deficient ether lipid biosynthesis in rhizomelic chondrodysplasia punctata and other disorders is associated with a wide range of severe symptoms including small stature with proximal shortening of the limbs, contractures, facial dysmorphism, congenital cataracts, ichthyosis, spasticity, microcephaly, and mental disability. Mouse models are available but show less severe symptoms. In both humans and mice, it has remained elusive which of the symptoms can be attributed to lack of plasmanyl or plasmenyl ether lipids. The latter compounds, better known as plasmalogens, harbor a vinyl ether double bond conferring special chemical and physical properties. Discrimination between plasmanyl and plasmenyl ether lipids is a major analytical challenge, especially in complex lipid extracts with many isobaric species. Consequently, these lipids are often neglected also in recent lipidomic studies. Here, we present a comprehensive LC–MS/MS based approach that allows unequivocal distinction of these two lipid subclasses based on their chromatographic properties. The method was validated using a novel plasmalogen-deficient mouse model, which lacks plasmanylethanolamine desaturase and therefore cannot form plasmenyl ether lipids. We demonstrate that plasmanylethanolamine desaturase deficiency causes an accumulation of plasmanyl species, a too little studied but biologically important substance class.
Highlights
Deficient ether lipid biosynthesis in rhizomelic chondrodysplasia punctata and other disorders is associated with a wide range of severe symptoms including small stature with proximal shortening of the limbs, contractures, facial dysmorphism, congenital cataracts, ichthyosis, spasticity, microcephaly, and mental disability
The biosynthesis of an ether lipid starts with the synthesis of 1-O-alkyl-glycero-3-phosphate in peroxisomes (Figure 1B) and is impaired in specific inherited enzyme/transporter deficiencies as well as peroxisome biogenesis disorders (Zellweger spectrum disorders).[3]
Plasmalogens are subsequently formed in the endoplasmic reticulum from 1-O-alkyl-PE precursors by the action of the enzyme plasmanylethanolamine desaturase (PEDS), which was only recently identified to be encoded by TMEM189.4,5
Summary
Deficient ether lipid biosynthesis in rhizomelic chondrodysplasia punctata and other disorders is associated with a wide range of severe symptoms including small stature with proximal shortening of the limbs, contractures, facial dysmorphism, congenital cataracts, ichthyosis, spasticity, microcephaly, and mental disability. Mouse models are available but show less severe symptoms In both humans and mice, it has remained elusive which of the symptoms can be attributed to lack of plasmanyl or plasmenyl ether lipids. Discrimination between plasmanyl and plasmenyl ether lipids is a major analytical challenge, especially in complex lipid extracts with many isobaric species These lipids are often neglected in recent lipidomic studies. In LC−MS/MS lipidomic experiments, this frequently leads to inaccurate or even incorrect annotations of lipid species This problem is aggravated by a restricted selection of commercially available plasmanyl and plasmenyl standards. Analytical Chemistry pubs.acs.org/ac and cannot distinguish between individual molecular species,[12] an important aspect that would be necessary to advance research in this field
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