title: Acadian variant of Fanconi syndrome is caused by mitochondrial respiratory chain complex I deficiency due to a non-coding mutation in complex I assembly factor NDUFAF6.
abstract: The Acadian variant of Fanconi Syndrome refers to a specific condition characterized by generalized proximal tubular dysfunction from birth, slowly progressive chronic kidney disease and pulmonary interstitial fibrosis. This condition occurs only in Acadians, a founder population in Nova Scotia, Canada. The genetic and molecular basis of this disease is unknown. We carried out whole exome and genome sequencing and found that nine affected individuals were homozygous for the ultra-rare non-coding variant chr8:96046914 T > C; rs575462405, whereas 13 healthy siblings were either heterozygotes or lacked the mutant allele. This variant is located in intron 2 of NDUFAF6 (NM_152416.3; c.298-768 T > C), 37 base pairs upstream from an alternative splicing variant in NDUFAF6 chr8:96046951 A > G; rs74395342 (c.298-731 A > G). NDUFAF6 encodes NADH:ubiquinone oxidoreductase complex assembly factor 6, also known as C8ORF38. We found that rs575462405-either alone or in combination with rs74395342-affects splicing and synthesis of NDUFAF6 isoforms. Affected kidney and lung showed specific loss of the mitochondria-located NDUFAF6 isoform and ultrastructural characteristics of mitochondrial dysfunction. Accordingly, affected tissues had defects in mitochondrial respiration and complex I biogenesis that were corrected with NDUFAF6 cDNA transfection. Our results demonstrate that the Acadian variant of Fanconi Syndrome results from mitochondrial respiratory chain complex I deficiency. This information may be used in the diagnosis and prevention of this disease in individuals and families of Acadian descent and broadens the spectrum of the clinical presentation of mitochondrial diseases, respiratory chain defects and defects of complex I specifically.
authors.affiliation: Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, 120 00 Prague 2, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Hartmannová
authors.affiliation: Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, 120 00 Prague 2, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Piherová
authors.affiliation: Institute of Physiology of the Czech Academy of Sciences, Vídeňská 1083, Prague, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Tauchmannová
authors.affiliation: Section on Nephrology, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, USA.
authors.forename: Kendrah
authors.initials: K
authors.lastname: Kidd
authors.affiliation: Section of Pediatric Nephrology, Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.|IWK Health Center, Halifax, Nova Scotia, Canada.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Acott
authors.affiliation: Section of Pediatric Nephrology, Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.|IWK Health Center, Halifax, Nova Scotia, Canada.
authors.forename: John F S
authors.initials: JF
authors.lastname: Crocker
authors.affiliation: Department of Pathology.
authors.forename: Youcef
authors.initials: Y
authors.lastname: Oussedik
authors.affiliation: Department of Pathology.
authors.forename: Marcel
authors.initials: M
authors.lastname: Mallet
authors.affiliation: Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, 120 00 Prague 2, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Hodaňová
authors.affiliation: Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, 120 00 Prague 2, Czech Republic.
authors.forename: Viktor
authors.initials: V
authors.lastname: Stránecký
authors.affiliation: Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, 120 00 Prague 2, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Přistoupilová
authors.affiliation: Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, 120 00 Prague 2, Czech Republic.
authors.forename: Veronika
authors.initials: V
authors.lastname: Barešová
authors.affiliation: Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, 120 00 Prague 2, Czech Republic.
authors.forename: Ivana
authors.initials: I
authors.lastname: Jedličková
authors.affiliation: Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, 120 00 Prague 2, Czech Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Živná
authors.affiliation: Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, 120 00 Prague 2, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Sovová
authors.affiliation: Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, 120 00 Prague 2, Czech Republic.
authors.forename: Helena
authors.initials: H
authors.lastname: Hůlková
authors.affiliation: Section on Nephrology, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, USA.
authors.forename: Vicki
authors.initials: V
authors.lastname: Robins
authors.affiliation: Institute of Physiology of the Czech Academy of Sciences, Vídeňská 1083, Prague, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Vrbacký
authors.affiliation: Institute of Physiology of the Czech Academy of Sciences, Vídeňská 1083, Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Pecina
authors.affiliation: Institute of Physiology of the Czech Academy of Sciences, Vídeňská 1083, Prague, Czech Republic.
authors.forename: Vilma
authors.initials: V
authors.lastname: Kaplanová
authors.affiliation: Institute of Physiology of the Czech Academy of Sciences, Vídeňská 1083, Prague, Czech Republic.
authors.forename: Josef
authors.initials: J
authors.lastname: Houštěk
authors.affiliation: Institute of Physiology of the Czech Academy of Sciences, Vídeňská 1083, Prague, Czech Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Mráček
authors.affiliation: Section of Pulmonology.
authors.forename: Yves
authors.initials: Y
authors.lastname: Thibeault
authors.affiliation: Section on Nephrology, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Bleyer
authors.affiliation: Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, 120 00 Prague 2, Czech Republic skmoch@lf1.cuni.cz.|Section on Nephrology, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, USA.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Kmoch
mesh_terms: D000328:Adult; D000483:Alleles; D002170:Canada; D002874:Chromosome Mapping; D042967:Electron Transport Complex I / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005198:Fanconi Syndrome / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation
chemical_list: D024101:Mitochondrial Proteins; C530233:NDUFAF6 protein, human; D042967:Electron Transport Complex I