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Human Molecular Genetics, 2003, Vol. 12, No. 15 1881-1895
DOI: 10.1093/hmg/ddg191
© 2003 Oxford University Press

Inactivation of ether lipid biosynthesis causes male infertility, defects in eye development and optic nerve hypoplasia in mice

Claus Rodemer1, Thanh-Phuong Thai2, Britta Brugger1, Thomas Kaercher3, Hauke Werner4, Klaus-Armin Nave5, Felix Wieland1, Karin Gorgas6 and Wilhelm W. Just1,*

1Universität Heidelberg, Biochemie-Zentrum Heidelberg (BZH), 69120 Heidelberg, Germany, 2Universitätsklinik, Abteilung für Innere Medizin, 69120 Heidelberg, Germany, 3Klinikum Ludwigshafen, 67063 Ludwigshafen, Germany, 4Yale University, School of Medicine, Department of Cell Biology, New Haven, CT, USA, 5Max-Planck-Institut für Experimentelle Medizin, Abteilung Neurogenetik, 37075 Göttingen, Germany and 6Institut für Anatomie und Zellbiologie der Universität, 69120 Heidelberg, Germany

Received March 20, 2003; Accepted May 28, 2003

Although known for almost 80 years, the physiological role of plasmalogens (PLs), the major mammalian ether lipids (ELs), is still enigmatic. Humans that lack ELs suffer from rhizomelic chondrodysplasia punctata (RCDP), a peroxisomal disorder usually resulting in death in early childhood. In order to learn more about the functions of ELs, we generated a mouse model for RCDP by a targeted disruption of the dihydroxyacetonephosphate acyltransferase gene. The mutant mice revealed multiple abnormalities, such as male infertility, defects in eye development, cataract and optic nerve hypoplasia, some of which were also observed in RCDP. Mass spectroscopic analysis demonstrated the presence of highly unsaturated fatty acids including docosahexaenoic acid (DHA) in brain PLs and the occurrence of PLs in lipid raft microdomains (LRMs) isolated from brain myelin. In mutants, PLs were completely absent and the concentration of brain DHA was reduced. The marker proteins flotillin-1 and F3/contactin were found in brain LRMs in reduced concentrations. In addition, the gap junctional protein connexin 43, known to be recruited to LRMs and essential for lens development and spermatogenesis, was down-regulated in embryonic fibroblasts of the EL-deficient mice. Free cholesterol, an important constituent of LRMs, was found in these fibroblasts to be accumulated in a perinuclear compartment. These data suggest that the EL-deficient mice allow the identification of new phenotypes not related so far to EL-deficiency (male sterility, defects in myelination and optic nerve hypoplasia) and indicate that PLs are required for the correct assembly and function of LRMs.

* To whom correspondence should be addressed at: Biochemie-Zentrum der Universität, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany. Tel: +49 6221544151; Fax: +49 6221544366; Email: wilhelm.just{at}urz.uni-heidelberg.de


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