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Primary coenzyme Q10 nephropathy, a potentially treatable form of steroid-resistant nephrotic syndrome

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Abstract

Steroid-resistant nephrotic syndrome (SRNS) is a genetically heterogeneous kidney disease that is the second most frequent cause of kidney failure in the first 2 decades of life. Despite the identification of mutations in more than 39 genes as causing SRNS, and the localization of its pathogenesis to glomerular podocytes, the disease mechanisms of SRNS remain poorly understood and no universally safe and effective therapy exists to treat patients with this condition. Recently, genetic research has identified a subgroup of SRNS patients whose kidney pathology is caused by primary coenzyme Q10 (CoQ10) deficiency due to recessive mutations in genes that encode proteins in the CoQ10 biosynthesis pathway. Clinical and preclinical studies show that primary CoQ10 deficiency may be responsive to treatment with CoQ10 supplements bypassing the biosynthesis defects. Coenzyme Q10 is an essential component of the mitochondrial respiratory chain, where it transports electrons from complexes I and II to complex III. Studies in yeast and mammalian model systems have recently identified the molecular functions of the individual CoQ10 biosynthesis complex proteins, validated these findings, and provided an impetus for developing therapeutic compounds to replenish CoQ10 levels in the tissues/organs and thus prevent the destruction of tissues due to mitochondrial OXPHOS deficiencies. In this review, we will summarize the clinical findings of the kidney pathophysiology of primary CoQ10 deficiencies and discuss recent advances in the development of therapies to counter CoQ10 deficiency in tissues.

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References

  1. El Bakkali L, Rodrigues Pereira R, Kuik DJ, Ket JC, van Wijk JA (2011) Nephrotic syndrome in The Netherlands: a population-based cohort study and a review of the literature. Pediatr Nephrol 26:1241–1246

    Article  PubMed  PubMed Central  Google Scholar 

  2. McKinney PA, Feltbower RG, Brocklebank JT, Fitzpatrick MM (2001) Time trends and ethnic patterns of childhood nephrotic syndrome in Yorkshire, UK. Pediatr Nephrol 16:1040–1044

    Article  CAS  PubMed  Google Scholar 

  3. Wyatt RJ, Marx MB, Kazee M, Holland NH (1982) Current estimates of the incidence of steroid responsive idiopathic nephrosis in Kentucky children 1-9 years of age. Int J Pediatr Nephrol 3:63–65

    CAS  PubMed  Google Scholar 

  4. Chanchlani R, Parekh RS (2016) Ethnic differences in childhood nephrotic syndrome. Front Pediatr 4:39

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kim JS, Bellew CA, Silverstein DM, Aviles DH, Boineau FG, Vehaskari VM (2005) High incidence of initial and late steroid resistance in childhood nephrotic syndrome. Kidney Int 68:1275–1281

    Article  CAS  PubMed  Google Scholar 

  6. Benoit G, Machuca E, Antignac C (2010) Hereditary nephrotic syndrome: a systematic approach for genetic testing and a review of associated podocyte gene mutations. Pediatr Nephrol 25:1621–1632

    Article  PubMed  PubMed Central  Google Scholar 

  7. Vivante A, Hildebrandt F (2016) Exploring the genetic basis of early-onset chronic kidney disease. Nat Rev Nephrol 12:133–146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Weaver DJ Jr, Somers MJG, Martz K, Mitsnefes MM (2017) Clinical outcomes and survival in pediatric patients initiating chronic dialysis: a report of the NAPRTCS registry. Pediatr Nephrol 32:2319–2330

    Article  PubMed  Google Scholar 

  9. Trautmann A, Bodria M, Ozaltin F, Gheisari A, Melk A, Azocar M, Anarat A, Caliskan S, Emma F, Gellermann J, Oh J, Baskin E, Ksiazek J, Remuzzi G, Erdogan O, Akman S, Dusek J, Davitaia T, Ozkaya O, Papachristou F, Firszt-Adamczyk A, Urasinski T, Testa S, Krmar RT, Hyla-Klekot L, Pasini A, Ozcakar ZB, Sallay P, Cakar N, Galanti M, Terzic J, Aoun B, Caldas Afonso A, Szymanik-Grzelak H, Lipska BS, Schnaidt S, Schaefer F, PodoNet Consortium (2015) Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort. Clin J Am Soc Nephrol 10:592–600

    Article  PubMed  PubMed Central  Google Scholar 

  10. Abe Y, Sakairi T, Kajiyama H, Shrivastav S, Beeson C, Kopp JB (2010) Bioenergetic characterization of mouse podocytes. Am J Physiol Cell Physiol 299:C464–C476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Brinkkoetter PT, Bork T, Salou S, Liang W, Mizi A, Ozel C, Koehler S, Hagmann HH, Ising C, Kuczkowski A, Schnyder S, Abed A, Schermer B, Benzing T, Kretz O, Puelles VG, Lagies S, Schlimpert M, Kammerer B, Handschin C, Schell C, Huber TB (2019) Anaerobic glycolysis maintains the glomerular filtration barrier independent of mitochondrial metabolism and dynamics. Cell Rep 27(1551–1566):e1555

    Google Scholar 

  12. Cil O, Perwad F (2018) Monogenic causes of proteinuria in children. Front Med (Lausanne) 5:55

    Article  Google Scholar 

  13. Preston R, Stuart HM, Lennon R (2019) Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how? Pediatr Nephrol 34:195–210

    Article  PubMed  Google Scholar 

  14. De Vriese AS, Sethi S, Nath KA, Glassock RJ, Fervenza FC (2018) Differentiating primary, genetic, and secondary FSGS in adults: a clinicopathologic approach. J Am Soc Nephrol 29:759–774

    Article  PubMed  PubMed Central  Google Scholar 

  15. Lopez LC, Schuelke M, Quinzii CM, Kanki T, Rodenburg RJ, Naini A, Dimauro S, Hirano M (2006) Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations. Am J Hum Genet 79:1125–1129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Diomedi-Camassei F, Di Giandomenico S, Santorelli FM, Caridi G, Piemonte F, Montini G, Ghiggeri GM, Murer L, Barisoni L, Pastore A, Muda AO, Valente ML, Bertini E, Emma F (2007) COQ2 nephropathy: a newly described inherited mitochondriopathy with primary renal involvement. J Am Soc Nephrol 18:2773–2780

    Article  CAS  PubMed  Google Scholar 

  17. Heeringa SF, Chernin G, Chaki M, Zhou W, Sloan AJ, Ji Z, Xie LX, Salviati L, Hurd TW, Vega-Warner V, Killen PD, Raphael Y, Ashraf S, Ovunc B, Schoeb DS, McLaughlin HM, Airik R, Vlangos CN, Gbadegesin R, Hinkes B, Saisawat P, Trevisson E, Doimo M, Casarin A, Pertegato V, Giorgi G, Prokisch H, Rotig A, Nurnberg G, Becker C, Wang S, Ozaltin F, Topaloglu R, Bakkaloglu A, Bakkaloglu SA, Muller D, Beissert A, Mir S, Berdeli A, Varpizen S, Zenker M, Matejas V, Santos-Ocana C, Navas P, Kusakabe T, Kispert A, Akman S, Soliman NA, Krick S, Mundel P, Reiser J, Nurnberg P, Clarke CF, Wiggins RC, Faul C, Hildebrandt F (2011) COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J Clin Invest 121:2013–2024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ashraf S, Gee HY, Woerner S, Xie LX, Vega-Warner V, Lovric S, Fang H, Song X, Cattran DC, Avila-Casado C, Paterson AD, Nitschke P, Bole-Feysot C, Cochat P, Esteve-Rudd J, Haberberger B, Allen SJ, Zhou W, Airik R, Otto EA, Barua M, Al-Hamed MH, Kari JA, Evans J, Bierzynska A, Saleem MA, Bockenhauer D, Kleta R, El Desoky S, Hacihamdioglu DO, Gok F, Washburn J, Wiggins RC, Choi M, Lifton RP, Levy S, Han Z, Salviati L, Prokisch H, Williams DS, Pollak M, Clarke CF, Pei Y, Antignac C, Hildebrandt F (2013) ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J Clin Invest 123:5179–5189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Atmaca M, Gulhan B, Korkmaz E, Inozu M, Soylemezoglu O, Candan C, Bayazit AK, Elmaci AM, Parmaksiz G, Duzova A, Besbas N, Topaloglu R, Ozaltin F (2017) Follow-up results of patients with ADCK4 mutations and the efficacy of CoQ10 treatment. Pediatr Nephrol 32:1369–1375

    Article  PubMed  Google Scholar 

  20. Atmaca M, Gulhan B, Atayar E, Bayazit AK, Candan C, Arici M, Topaloglu R, Ozaltin F (2019) Long-term follow-up results of patients with ADCK4 mutations who have been diagnosed in the asymptomatic period: effects of early initiation of CoQ10 supplementation. Turk J Pediatr 61:657–663

    Article  PubMed  Google Scholar 

  21. Korkmaz E, Lipska-Zietkiewicz BS, Boyer O, Gribouval O, Fourrage C, Tabatabaei M, Schnaidt S, Gucer S, Kaymaz F, Arici M, Dinckan A, Mir S, Bayazit AK, Emre S, Balat A, Rees L, Shroff R, Bergmann C, Mourani C, Antignac C, Ozaltin F, Schaefer F, PodoNet Consortium (2016) ADCK4-associated glomerulopathy causes adolescence-onset FSGS. J Am Soc Nephrol 27:63–68

    Article  CAS  PubMed  Google Scholar 

  22. Ogasahara S, Engel AG, Frens D, Mack D (1989) Muscle coenzyme Q deficiency in familial mitochondrial encephalomyopathy. Proc Natl Acad Sci U S A 86:2379–2382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rotig A, Appelkvist EL, Geromel V, Chretien D, Kadhom N, Edery P, Lebideau M, Dallner G, Munnich A, Ernster L, Rustin P (2000) Quinone-responsive multiple respiratory-chain dysfunction due to widespread coenzyme Q10 deficiency. Lancet 356:391–395

    Article  CAS  PubMed  Google Scholar 

  24. Lamperti C, Naini A, Hirano M, De Vivo DC, Bertini E, Servidei S, Valeriani M, Lynch D, Banwell B, Berg M, Dubrovsky T, Chiriboga C, Angelini C, Pegoraro E, DiMauro S (2003) Cerebellar ataxia and coenzyme Q10 deficiency. Neurology 60:1206–1208

    Article  CAS  PubMed  Google Scholar 

  25. Van Maldergem L, Trijbels F, DiMauro S, Sindelar PJ, Musumeci O, Janssen A, Delberghe X, Martin JJ, Gillerot Y (2002) Coenzyme Q-responsive Leigh’s encephalopathy in two sisters. Ann Neurol 52:750–754

    Article  PubMed  CAS  Google Scholar 

  26. Lalani SR, Vladutiu GD, Plunkett K, Lotze TE, Adesina AM, Scaglia F (2005) Isolated mitochondrial myopathy associated with muscle coenzyme Q10 deficiency. Arch Neurol 62:317–320

    Article  PubMed  Google Scholar 

  27. Alcazar-Fabra M, Navas P, Brea-Calvo G (2016) Coenzyme Q biosynthesis and its role in the respiratory chain structure. Biochim Biophys Acta 1857:1073–1078

    Article  CAS  PubMed  Google Scholar 

  28. Zhang Y, Aberg F, Appelkvist EL, Dallner G, Ernster L (1995) Uptake of dietary coenzyme Q supplement is limited in rats. J Nutr 125:446–453

    CAS  PubMed  Google Scholar 

  29. Turunen M, Olsson J, Dallner G (2004) Metabolism and function of coenzyme Q. Biochim Biophys Acta 1660:171–199

    Article  CAS  PubMed  Google Scholar 

  30. Bhagavan HN, Chopra RK (2007) Plasma coenzyme Q10 response to oral ingestion of coenzyme Q10 formulations. Mitochondrion 7(Suppl):S78–S88

    Article  CAS  PubMed  Google Scholar 

  31. Stefely JA, Pagliarini DJ (2017) Biochemistry of mitochondrial coenzyme Q biosynthesis. Trends Biochem Sci 42:824–843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Desbats MA, Lunardi G, Doimo M, Trevisson E, Salviati L (2015) Genetic bases and clinical manifestations of coenzyme Q10 (CoQ 10) deficiency. J Inherit Metab Dis 38:145–156

    Article  CAS  PubMed  Google Scholar 

  33. Payet LA, Leroux M, Willison JC, Kihara A, Pelosi L, Pierrel F (2016) Mechanistic details of early steps in coenzyme Q biosynthesis pathway in yeast. Cell Chem Biol 23:1241–1250

    Article  CAS  PubMed  Google Scholar 

  34. Awad AM, Bradley MC, Fernandez-Del-Rio L, Nag A, Tsui HS, Clarke CF (2018) Coenzyme Q10 deficiencies: pathways in yeast and humans. Essays Biochem 62:361–376

    Article  PubMed  PubMed Central  Google Scholar 

  35. Bentinger M, Tekle M, Dallner G (2010) Coenzyme Q--biosynthesis and functions. Biochem Biophys Res Commun 396:74–79

    Article  CAS  PubMed  Google Scholar 

  36. Watmough NJ, Frerman FE (2010) The electron transfer flavoprotein: ubiquinone oxidoreductases. Biochim Biophys Acta 1797:1910–1916

    Article  CAS  PubMed  Google Scholar 

  37. Lopez LC, Luna-Sanchez M, Garcia-Corzo L, Quinzii CM, Hirano M (2014) Pathomechanisms in coenzyme q10-deficient human fibroblasts. Mol Syndromol 5:163–169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bentinger M, Brismar K, Dallner G (2007) The antioxidant role of coenzyme Q. Mitochondrion 7(Suppl):S41–S50

    Article  CAS  PubMed  Google Scholar 

  39. Quinzii CM, Garone C, Emmanuele V, Tadesse S, Krishna S, Dorado B, Hirano M (2013) Tissue-specific oxidative stress and loss of mitochondria in CoQ-deficient Pdss2 mutant mice. FASEB J 27:612–621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Garcia-Corzo L, Luna-Sanchez M, Doerrier C, Garcia JA, Guaras A, Acin-Perez R, Bullejos-Peregrin J, Lopez A, Escames G, Enriquez JA, Acuna-Castroviejo D, Lopez LC (2013) Dysfunctional Coq9 protein causes predominant encephalomyopathy associated with CoQ deficiency. Hum Mol Genet 22:1233–1248

    Article  CAS  PubMed  Google Scholar 

  41. Quinzii CM, Lopez LC, Von-Moltke J, Naini A, Krishna S, Schuelke M, Salviati L, Navas P, DiMauro S, Hirano M (2008) Respiratory chain dysfunction and oxidative stress correlate with severity of primary CoQ10 deficiency. FASEB J 22:1874–1885

    Article  CAS  PubMed  Google Scholar 

  42. Ziosi M, Di Meo I, Kleiner G, Gao XH, Barca E, Sanchez-Quintero MJ, Tadesse S, Jiang H, Qiao C, Rodenburg RJ, Scalais E, Schuelke M, Willard B, Hatzoglou M, Tiranti V, Quinzii CM (2017) Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway. EMBO Mol Med 9:96–111

    Article  CAS  PubMed  Google Scholar 

  43. Ernster L, Dallner G (1995) Biochemical, physiological and medical aspects of ubiquinone function. Biochim Biophys Acta 1271:195–204

    Article  PubMed  Google Scholar 

  44. Lopez-Martin JM, Salviati L, Trevisson E, Montini G, DiMauro S, Quinzii C, Hirano M, Rodriguez-Hernandez A, Cordero MD, Sanchez-Alcazar JA, Santos-Ocana C, Navas P (2007) Missense mutation of the COQ2 gene causes defects of bioenergetics and de novo pyrimidine synthesis. Hum Mol Genet 16:1091–1097

    Article  CAS  PubMed  Google Scholar 

  45. Quinzii C, Naini A, Salviati L, Trevisson E, Navas P, Dimauro S, Hirano M (2006) A mutation in para-hydroxybenzoate-polyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency. Am J Hum Genet 78:345–349

    Article  CAS  PubMed  Google Scholar 

  46. Vasta V, Merritt JL 2nd, Saneto RP, Hahn SH (2012) Next-generation sequencing for mitochondrial diseases: a wide diagnostic spectrum. Pediatr Int 54:585–601

    Article  CAS  PubMed  Google Scholar 

  47. Sadowski CE, Lovric S, Ashraf S, Pabst WL, Gee HY, Kohl S, Engelmann S, Vega-Warner V, Fang H, Halbritter J, Somers MJ, Tan W, Shril S, Fessi I, Lifton RP, Bockenhauer D, El-Desoky S, Kari JA, Zenker M, Kemper MJ, Mueller D, Fathy HM, Soliman NA, Group SS, Hildebrandt F (2015) A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. J Am Soc Nephrol 26:1279–1289

    Article  CAS  PubMed  Google Scholar 

  48. Ivanyi B, Racz GZ, Gal P, Brinyiczki K, Bodi I, Kalmar T, Maroti Z, Bereczki C (2018) Diffuse mesangial sclerosis in a PDSS2 mutation-induced coenzyme Q10 deficiency. Pediatr Nephrol 33:439–446

    Article  PubMed  Google Scholar 

  49. Montini G, Malaventura C, Salviati L (2008) Early coenzyme Q10 supplementation in primary coenzyme Q10 deficiency. N Engl J Med 358:2849–2850

    Article  CAS  PubMed  Google Scholar 

  50. Mollet J, Giurgea I, Schlemmer D, Dallner G, Chretien D, Delahodde A, Bacq D, de Lonlay P, Munnich A, Rotig A (2007) Prenyldiphosphate synthase, subunit 1 (PDSS1) and OH-benzoate polyprenyltransferase (COQ2) mutations in ubiquinone deficiency and oxidative phosphorylation disorders. J Clin Invest 117:765–772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. McCarthy HJ, Bierzynska A, Wherlock M, Ognjanovic M, Kerecuk L, Hegde S, Feather S, Gilbert RD, Krischock L, Jones C, Sinha MD, Webb NJ, Christian M, Williams MM, Marks S, Koziell A, Welsh GI, Saleem MA, RADAR the UK SRNS Study Group (2013) Simultaneous sequencing of 24 genes associated with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 8:637–648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Gigante M, Diella S, Santangelo L, Trevisson E, Acosta MJ, Amatruda M, Finzi G, Caridi G, Murer L, Accetturo M, Ranieri E, Ghiggeri GM, Giordano M, Grandaliano G, Salviati L, Gesualdo L (2017) Further phenotypic heterogeneity of CoQ10 deficiency associated with steroid resistant nephrotic syndrome and novel COQ2 and COQ6 variants. Clin Genet 92:224–226

    Article  CAS  PubMed  Google Scholar 

  53. Starr MC, Chang IJ, Finn LS, Sun A, Larson AA, Goebel J, Hanevold C, Thies J, Van Hove JLK, Hingorani SR, Lam C (2018) COQ2 nephropathy: a treatable cause of nephrotic syndrome in children. Pediatr Nephrol 33:1257–1261

    Article  PubMed  PubMed Central  Google Scholar 

  54. Eroglu FK, Ozaltin F, Gonc N, Nalcacioglu H, Ozcakar ZB, Yalnizoglu D, Gucer S, Orhan D, Eminoglu FT, Gocmen R, Alikasifoglu A, Topaloglu R, Duzova A (2018) Response to early coenzyme Q10 supplementation is not sustained in CoQ10 deficiency caused by CoQ2 mutation. Pediatr Neurol 88:71–74

    Article  PubMed  Google Scholar 

  55. Nakanishi K, Okamoto T, Nozu K, Hara S, Sato Y, Hayashi A, Takahashi T, Nagano C, Sakakibara N, Horinouchi T, Fujimura J, Minamikawa S, Yamamura T, Rossanti R, Nagase H, Kaito H, Ariga T, Iijima K (2019) Pair analysis and custom array CGH can detect a small copy number variation in COQ6 gene. Clin Exp Nephrol 23:669–675

    Article  CAS  PubMed  Google Scholar 

  56. Park E, Ahn YH, Kang HG, Yoo KH, Won NH, Lee KB, Moon KC, Seong MW, Gwon TR, Park SS, Cheong HI (2017) COQ6 mutations in children with steroid-resistant focal segmental glomerulosclerosis and Sensorineural hearing loss. Am J Kidney Dis 70:139–144

    Article  CAS  PubMed  Google Scholar 

  57. Stanczyk M, Balasz-Chmielewska I, Lipska-Zietkiewicz B, Tkaczyk M (2018) CoQ10-related sustained remission of proteinuria in a child with COQ6 glomerulopathy-a case report. Pediatr Nephrol 33:2383–2387

    Article  PubMed  PubMed Central  Google Scholar 

  58. Yuruk Yildirim Z, Toksoy G, Uyguner O, Nayir A, Yavuz S, Altunoglu U, Turkkan ON, Sevinc B, Gokcay G, Kurkcu Gunes D, Kiyak A, Yilmaz A (2020) Primary coenzyme Q10 Deficiency-6 (COQ10D6): two siblings with variable expressivity of the renal phenotype. Eur J Med Genet 63:103621

    Article  PubMed  Google Scholar 

  59. Justine Perrin R, Rousset-Rouviere C, Garaix F, Cano A, Conrath J, Boyer O, Tsimaratos M (2020) COQ6 mutation in patients with nephrotic syndrome, sensorineural deafness, and optic atrophy. JIMD Rep 54:37–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang F, Zhang Y, Mao J, Yu Z, Yi Z, Yu L, Sun J, Wei X, Ding F, Zhang H, Xiao H, Yao Y, Tan W, Lovric S, Ding J, Hildebrandt F (2017) Spectrum of mutations in Chinese children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 32:1181–1192

    Article  PubMed  PubMed Central  Google Scholar 

  61. Feng C, Wang Q, Wang J, Liu F, Shen H, Fu H, Mao J (2017) Coenzyme Q10 supplementation therapy for 2 children with proteinuria renal disease and ADCK4 mutation: case reports and literature review. Medicine (Baltimore) 96:e8880

    Article  CAS  Google Scholar 

  62. Lolin K, Chiodini BD, Hennaut E, Adams B, Dahan K, Ismaili K (2017) Early-onset of ADCK4 glomerulopathy with renal failure: a case report. BMC Med Genet 18:28

    Article  PubMed  PubMed Central  Google Scholar 

  63. Yang J, Yang Y, Hu Z (2018) A novel ADCK4 mutation in a Chinese family with ADCK4-associated glomerulopathy. Biochem Biophys Res Commun 506:444–449

    Article  CAS  PubMed  Google Scholar 

  64. Park E, Kang HG, Choi YH, Lee KB, Moon KC, Jeong HJ, Nagata M, Cheong HI (2017) Focal segmental glomerulosclerosis and medullary nephrocalcinosis in children with ADCK4 mutations. Pediatr Nephrol 32:1547–1554

    Article  PubMed  Google Scholar 

  65. Warejko JK, Tan W, Daga A, Schapiro D, Lawson JA, Shril S, Lovric S, Ashraf S, Rao J, Hermle T, Jobst-Schwan T, Widmeier E, Majmundar AJ, Schneider R, Gee HY, Schmidt JM, Vivante A, van der Ven AT, Ityel H, Chen J, Sadowski CE, Kohl S, Pabst WL, Nakayama M, Somers MJG, Rodig NM, Daouk G, Baum M, Stein DR, Ferguson MA, Traum AZ, Soliman NA, Kari JA, El Desoky S, Fathy H, Zenker M, Bakkaloglu SA, Muller D, Noyan A, Ozaltin F, Cadnapaphornchai MA, Hashmi S, Hopcian J, Kopp JB, Benador N, Bockenhauer D, Bogdanovic R, Stajic N, Chernin G, Ettenger R, Fehrenbach H, Kemper M, Munarriz RL, Podracka L, Buscher R, Serdaroglu E, Tasic V, Mane S, Lifton RP, Braun DA, Hildebrandt F (2018) Whole exome sequencing of patients with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 13:53–62

    Article  CAS  PubMed  Google Scholar 

  66. Forsgren M, Attersand A, Lake S, Grunler J, Swiezewska E, Dallner G, Climent I (2004) Isolation and functional expression of human COQ2, a gene encoding a polyprenyl transferase involved in the synthesis of CoQ. Biochem J 382:519–526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Salviati L, Sacconi S, Murer L, Zacchello G, Franceschini L, Laverda AM, Basso G, Quinzii C, Angelini C, Hirano M, Naini AB, Navas P, DiMauro S, Montini G (2005) Infantile encephalomyopathy and nephropathy with CoQ10 deficiency: a CoQ10-responsive condition. Neurology 65:606–608

    Article  CAS  PubMed  Google Scholar 

  68. Desbats MA, Morbidoni V, Silic-Benussi M, Doimo M, Ciminale V, Cassina M, Sacconi S, Hirano M, Basso G, Pierrel F, Navas P, Salviati L, Trevisson E (2016) The COQ2 genotype predicts the severity of coenzyme Q10 deficiency. Hum Mol Genet 25:4256–4265

    Article  CAS  PubMed  Google Scholar 

  69. Widmeier E, Yu S, Nag A, Chung YW, Nakayama M, Fernandez-Del-Rio L, Hugo H, Schapiro D, Buerger F, Choi WI, Helmstadter M, Kim JW, Ryu JH, Lee MG, Clarke CF, Hildebrandt F, Gee HY (2020) ADCK4 deficiency destabilizes the coenzyme Q complex, which is rescued by 2,4-dihydroxybenzoic acid treatment. J Am Soc Nephrol 31:1191–1211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wu L, Zhang Q, Mo W, Feng J, Li S, Li J, Liu T, Xu S, Wang W, Lu X, Yu Q, Chen K, Xia Y, Lu J, Xu L, Zhou Y, Fan X, Guo C (2017) Quercetin prevents hepatic fibrosis by inhibiting hepatic stellate cell activation and reducing autophagy via the TGF-beta1/Smads and PI3K/Akt pathways. Sci Rep 7:9289

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Vazquez Fonseca L, Doimo M, Calderan C, Desbats MA, Acosta MJ, Cerqua C, Cassina M, Ashraf S, Hildebrandt F, Sartori G, Navas P, Trevisson E, Salviati L (2018) Mutations in COQ8B (ADCK4) found in patients with steroid-resistant nephrotic syndrome alter COQ8B function. Hum Mutat 39:406–414

    Article  CAS  PubMed  Google Scholar 

  72. Freyer C, Stranneheim H, Naess K, Mourier A, Felser A, Maffezzini C, Lesko N, Bruhn H, Engvall M, Wibom R, Barbaro M, Hinze Y, Magnusson M, Andeer R, Zetterstrom RH, von Dobeln U, Wredenberg A, Wedell A (2015) Rescue of primary ubiquinone deficiency due to a novel COQ7 defect using 2,4-dihydroxybensoic acid. J Med Genet 52:779–783

    Article  CAS  PubMed  Google Scholar 

  73. Kwong AK, Chiu AT, Tsang MH, Lun KS, Rodenburg RJT, Smeitink J, Chung BH, Fung CW (2019) A fatal case of COQ7-associated primary coenzyme Q10 deficiency. JIMD Rep 47:23–29

    Article  PubMed  PubMed Central  Google Scholar 

  74. Duncan AJ, Bitner-Glindzicz M, Meunier B, Costello H, Hargreaves IP, Lopez LC, Hirano M, Quinzii CM, Sadowski MI, Hardy J, Singleton A, Clayton PT, Rahman S (2009) A nonsense mutation in COQ9 causes autosomal-recessive neonatal-onset primary coenzyme Q10 deficiency: a potentially treatable form of mitochondrial disease. Am J Hum Genet 84:558–566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Lyon MF, Hulse EV (1971) An inherited kidney disease of mice resembling human nephronophthisis. J Med Genet 8:41–48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Peng M, Jarett L, Meade R, Madaio MP, Hancock WW, George AL Jr, Neilson EG, Gasser DL (2004) Mutant prenyltransferase-like mitochondrial protein (PLMP) and mitochondrial abnormalities in kd/kd mice. Kidney Int 66:20–28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Barisoni L, Madaio MP, Eraso M, Gasser DL, Nelson PJ (2005) The kd/kd mouse is a model of collapsing glomerulopathy. J Am Soc Nephrol 16:2847–2851

    Article  PubMed  Google Scholar 

  78. Peng M, Falk MJ, Haase VH, King R, Polyak E, Selak M, Yudkoff M, Hancock WW, Meade R, Saiki R, Lunceford AL, Clarke CF, Gasser DL (2008) Primary coenzyme Q deficiency in Pdss2 mutant mice causes isolated renal disease. PLoS Genet 4:e1000061

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Luna-Sanchez M, Diaz-Casado E, Barca E, Tejada MA, Montilla-Garcia A, Cobos EJ, Escames G, Acuna-Castroviejo D, Quinzii CM, Lopez LC (2015) The clinical heterogeneity of coenzyme Q10 deficiency results from genotypic differences in the Coq9 gene. EMBO Mol Med 7:670–687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Widmeier E, Airik M, Hugo H, Schapiro D, Wedel J, Ghosh CC, Nakayama M, Schneider R, Awad AM, Nag A, Cho J, Schueler M, Clarke CF, Airik R, Hildebrandt F (2019) Treatment with 2,4-dihydroxybenzoic acid prevents FSGS progression and renal fibrosis in podocyte-specific Coq6 knockout mice. J Am Soc Nephrol 30:393–405

    Article  CAS  PubMed Central  Google Scholar 

  81. Gee HY, Otto EA, Hurd TW, Ashraf S, Chaki M, Cluckey A, Vega-Warner V, Saisawat P, Diaz KA, Fang H, Kohl S, Allen SJ, Airik R, Zhou W, Ramaswami G, Janssen S, Fu C, Innis JL, Weber S, Vester U, Davis EE, Katsanis N, Fathy HM, Jeck N, Klaus G, Nayir A, Rahim KA, Al Attrach I, Al Hassoun I, Ozturk S, Drozdz D, Helmchen U, O'Toole JF, Attanasio M, Lewis RA, Nurnberg G, Nurnberg P, Washburn J, MacDonald J, Innis JW, Levy S, Hildebrandt F (2014) Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies. Kidney Int 85:880–887

    Article  CAS  PubMed  Google Scholar 

  82. Wang Y, Oxer D, Hekimi S (2015) Mitochondrial function and lifespan of mice with controlled ubiquinone biosynthesis. Nat Commun 6:6393

    Article  CAS  PubMed  Google Scholar 

  83. Hargreaves IP (2014) Coenzyme Q10 as a therapy for mitochondrial disease. Int J Biochem Cell Biol 49:105–111

    Article  CAS  PubMed  Google Scholar 

  84. Ozeir M, Muhlenhoff U, Webert H, Lill R, Fontecave M, Pierrel F (2011) Coenzyme Q biosynthesis: Coq6 is required for the C5-hydroxylation reaction and substrate analogs rescue Coq6 deficiency. Chem Biol 18:1134–1142

    Article  CAS  PubMed  Google Scholar 

  85. Doimo M, Trevisson E, Airik R, Bergdoll M, Santos-Ocana C, Hildebrandt F, Navas P, Pierrel F, Salviati L (2014) Effect of vanillic acid on COQ6 mutants identified in patients with coenzyme Q10 deficiency. Biochim Biophys Acta 1842:1–6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hermle T, Braun DA, Helmstadter M, Huber TB, Hildebrandt F (2017) Modeling monogenic human nephrotic syndrome in the Drosophila garland cell nephrocyte. J Am Soc Nephrol 28:1521–1533

    Article  CAS  PubMed  Google Scholar 

  87. Acosta Lopez MJ, Trevisson E, Canton M, Vazquez-Fonseca L, Morbidoni V, Baschiera E, Frasson C, Pelosi L, Rascalou B, Desbats MA, Alcazar-Fabra M, Rios JJ, Sanchez-Garcia A, Basso G, Navas P, Pierrel F, Brea-Calvo G, Salviati L (2019) Vanillic acid restores coenzyme Q biosynthesis and ATP production in human cells lacking COQ6. Oxidative Med Cell Longev 2019:3904905

    Article  CAS  Google Scholar 

  88. Wang Y, Smith C, Parboosingh JS, Khan A, Innes M, Hekimi S (2017) Pathogenicity of two COQ7 mutations and responses to 2,4-dihydroxybenzoate bypass treatment. J Cell Mol Med 21:2329–2343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Sobreira C, Hirano M, Shanske S, Keller RK, Haller RG, Davidson E, Santorelli FM, Miranda AF, Bonilla E, Mojon DS, Barreira AA, King MP, DiMauro S (1997) Mitochondrial encephalomyopathy with coenzyme Q10 deficiency. Neurology 48:1238–1243

    Article  CAS  PubMed  Google Scholar 

  90. Lopez-Lluch G, Del Pozo-Cruz J, Sanchez-Cuesta A, Cortes-Rodriguez AB, Navas P (2019) Bioavailability of coenzyme Q10 supplements depends on carrier lipids and solubilization. Nutrition 57:133–140

    Article  CAS  PubMed  Google Scholar 

  91. Zaki NM (2016) Strategies for oral delivery and mitochondrial targeting of CoQ10. Drug Deliv 23:1868–1881

    CAS  PubMed  Google Scholar 

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Funding

This study was supported by the National Institutes of Health to RA (DK115403, P30DK079307).

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Authors and Affiliations

  1. Division of Nephrology, Department of Pediatrics, Massachusetts General Hospital for Children, Boston, MA, USA

    Weizhen Tan

  2. Division of Nephrology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA

    Rannar Airik

  3. Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA, USA

    Rannar Airik

  4. UPMC Children’s Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA

    Rannar Airik

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  1. Weizhen Tan
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Tan, W., Airik, R. Primary coenzyme Q10 nephropathy, a potentially treatable form of steroid-resistant nephrotic syndrome. Pediatr Nephrol 36, 3515–3527 (2021). https://doi.org/10.1007/s00467-020-04914-8

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  • DOI: https://doi.org/10.1007/s00467-020-04914-8

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