Identification of G8969>A in mitochondrial ATP6 gene that severely compromises ATP synthase function in a patient with IgA nephropathy.
Here we elucidated the pathogenesis of a 14-year-old Chinese female who initially developed an isolated nephropathy followed by a complex clinical presentation with brain and muscle problems, which indicated that the disease process was possibly due to a mitochondrial dysfunction. Careful evaluation of renal biopsy samples revealed a decreased staining of cells induced by COX and NADH dehydrogenase activities, and a strong fragmentation of the mitochondrial network. These anomalies were due to the presence of a mutation in the mitochondrial ATP6 gene, G8969>A. This mutation leads to replacement of a highly conserved serine residue at position 148 of the a-subunit of ATP synthase. Increasing the mutation load in cybrid cell lines was paralleled by the appearance of abnormal mitochondrial morphologies, diminished respiration and enhanced production of reactive oxygen species. An equivalent of the G8969>A mutation in yeast had dramatic consequences on ATP synthase, with a block in proton translocation. The mutation was particularly abundant (89%) in the kidney compared to blood and urine, which is likely the reason why this organ was affected first. Based on these findings, we suggest that nephrologists should pay more attention to the possibility of a mitochondrial dysfunction when evaluating patients suffering from kidney problems.
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
Shuzhen
S
Wen
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
Katarzyna
K
Niedzwiecka
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
Weiwei
W
Zhao
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
Shutian
S
Xu
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
Shaoshan
S
Liang
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
Xiaodong
X
Zhu
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
Honglang
H
Xie
CNRS, Institut de Biochimie et Génétique Cellulaires, UMR 5095, F-33077 Bordeaux, France.|Université de Bordeaux, IBGC, UMR 5095, F-33077 Bordeaux, France.|INSERM, Institut de Biochimie et Génétique Cellulaires, F-33077 Bordeaux, France.
Déborah
D
Tribouillard-Tanvier
CNRS, Institut de Biochimie et Génétique Cellulaires, UMR 5095, F-33077 Bordeaux, France.|Université de Bordeaux, IBGC, UMR 5095, F-33077 Bordeaux, France.
Marie-France
MF
Giraud
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
Caihong
C
Zeng
CNRS, Institut de Biochimie et Génétique Cellulaires, UMR 5095, F-33077 Bordeaux, France.|Université de Bordeaux, IBGC, UMR 5095, F-33077 Bordeaux, France.
Alain
A
Dautant
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
Róża
R
Kucharczyk
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
Zhihong
Z
Liu
CNRS, Institut de Biochimie et Génétique Cellulaires, UMR 5095, F-33077 Bordeaux, France.|Université de Bordeaux, IBGC, UMR 5095, F-33077 Bordeaux, France.
Jean-Paul
JP
di Rago
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
Huimei
H
Chen
D000293:Adolescent; D002460:Cell Line; D005260:Female; D020022:Genetic Predisposition to Disease; D005922:Glomerulonephritis, IGA / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008958:Models, Molecular; D020641:Polymorphism, Single Nucleotide; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D012694:Serine / Q000235:genetics
C501005:MT-ATP6 protein, human; D029701:Saccharomyces cerevisiae Proteins; D012694:Serine; D025261:Mitochondrial Proton-Translocating ATPases