title: Fabry disease: renal sphingolipid distribution in the α-Gal A knockout mouse model by mass spectrometric and immunohistochemical imaging.
abstract: Fabry disease is an X-linked lysosomal storage disease due to deficient α-galactosidase A (α-Gal A) activity and the resultant lysosomal accumulation of globotriaosylceramide (Gb3) and related lipids primarily in blood vessels, kidney, heart, and other organs. The renal distribution of stored glycolipid species in the α-Gal A knockout mouse model was compared to that in mice to assess relative distribution and absolute amounts of accumulated sphingolipid isoforms. Twenty isoforms of five sphingolipid groups were visualized by mass spectrometry imaging (MSI), and their distribution was compared with immunohistochemical (IHC) staining of Gb3, the major stored glycosphingolipid in consecutive tissue sections. Quantitative bulk lipid analysis of tissue sections was assessed by electrospray ionization with tandem mass spectrometry (ESI-MS/MS). In contrast to the findings in wild-type mice, all three analytical techniques (MSI, IHC, and ESI-MS/MS) revealed increases in Gb3 isoforms and ceramide dihexosides (composed mostly of galabiosylceramides), respectively. To our knowledge, this is the first report of the distribution of individual molecular species of Gb3 and galabiosylceramides in kidney sections in Fabry disease mouse. In addition, the spatial distribution of ceramides, ceramide monohexosides, and sphingomyelin forms in renal tissue is presented and discussed in the context of their biosynthesis.
authors.affiliation: Institute of Inherited Metabolic Disorders, Charles University in Prague, Ke Karlovu 2, 128 08, Prague 2, Czech Republic.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Kuchar
authors.forename: Helena
authors.initials: H
authors.lastname: Faltyskova
authors.forename: Lukas
authors.initials: L
authors.lastname: Krasny
authors.forename: Robert
authors.initials: R
authors.lastname: Dobrovolny
authors.forename: Helena
authors.initials: H
authors.lastname: Hulkova
authors.forename: Jana
authors.initials: J
authors.lastname: Ledvinova
authors.forename: Michael
authors.initials: M
authors.lastname: Volny
authors.forename: Martin
authors.initials: M
authors.lastname: Strohalm
authors.forename: Karel
authors.initials: K
authors.lastname: Lemr
authors.forename: Lenka
authors.initials: L
authors.lastname: Kryspinova
authors.forename: Befekadu
authors.initials: B
authors.lastname: Asfaw
authors.forename: Jitka
authors.initials: J
authors.lastname: Rybová
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
authors.forename: Vladimir
authors.initials: V
authors.lastname: Havlicek
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D000795:Fabry Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007120:Immunochemistry; D007668:Kidney / Q000737:chemistry* / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D013107:Sphingolipids / Q000737:chemistry / Q000378:metabolism*; D000519:alpha-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D013107:Sphingolipids; D000519:alpha-Galactosidase