title: Primary coenzyme Q deficiency in Pdss2 mutant mice causes isolated renal disease.
abstract: Coenzyme Q (CoQ) is an essential electron carrier in the respiratory chain whose deficiency has been implicated in a wide variety of human mitochondrial disease manifestations. Its multi-step biosynthesis involves production of polyisoprenoid diphosphate in a reaction that requires the enzymes be encoded by PDSS1 and PDSS2. Homozygous mutations in either of these genes, in humans, lead to severe neuromuscular disease, with nephrotic syndrome seen in PDSS2 deficiency. We now show that a presumed autoimmune kidney disease in mice with the missense Pdss2(kd/kd) genotype can be attributed to a mitochondrial CoQ biosynthetic defect. Levels of CoQ9 and CoQ10 in kidney homogenates from B6.Pdss2(kd/kd) mutants were significantly lower than those in B6 control mice. Disease manifestations originate specifically in glomerular podocytes, as renal disease is seen in Podocin/cre,Pdss2(loxP/loxP) knockout mice but not in conditional knockouts targeted to renal tubular epithelium, monocytes, or hepatocytes. Liver-conditional B6.Alb/cre,Pdss2(loxP/loxP) knockout mice have no overt disease despite demonstration that their livers have undetectable CoQ9 levels, impaired respiratory capacity, and significantly altered intermediary metabolism as evidenced by transcriptional profiling and amino acid quantitation. These data suggest that disease manifestations of CoQ deficiency relate to tissue-specific respiratory capacity thresholds, with glomerular podocytes displaying the greatest sensitivity to Pdss2 impairment.
authors.affiliation: Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: Peng
authors.forename: Marni J
authors.initials: MJ
authors.lastname: Falk
authors.forename: Volker H
authors.initials: VH
authors.lastname: Haase
authors.forename: Rhonda
authors.initials: R
authors.lastname: King
authors.forename: Erzsebet
authors.initials: E
authors.lastname: Polyak
authors.forename: Mary
authors.initials: M
authors.lastname: Selak
authors.forename: Marc
authors.initials: M
authors.lastname: Yudkoff
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
authors.forename: Ray
authors.initials: R
authors.lastname: Meade
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Saiki
authors.forename: Adam L
authors.initials: AL
authors.lastname: Lunceford
authors.forename: Catherine F
authors.initials: CF
authors.lastname: Clarke
authors.forename: David L
authors.initials: DL
authors.lastname: Gasser
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004579:Electron Transport; D020869:Gene Expression Profiling; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008930:Mitochondria, Liver / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D014451:Ubiquinone / Q000172:deficiency*
chemical_list: D017931:DNA Primers; D014451:Ubiquinone; D019883:Alkyl and Aryl Transferases; C573473:prenyl diphosphate synthase subunit 2, mouse