Abstract
Fanconi syndrome is a functional disorder of the proximal tubule, characterized by pan-aminoaciduria, glucosuria, hypophosphatemia, and metabolic acidosis. With the advancements in gene analysis technologies, several causative genes are identified for Fanconi syndrome. Several mitochondrial diseases cause Fanconi syndrome and various systemic symptoms; however, it is rare that the main clinical symptoms in such disorders are Fanconi syndrome without systematic active diseases like encephalomyopathy or cardiomyopathy. In this study, we analyzed two families exhibiting Fanconi syndrome, developmental disability and mildly elevated liver enzyme levels. Whole-exome sequencing (WES) detected compound heterozygous known and novel BCS1L mutations, which affect the assembly of mitochondrial respiratory chain complex III, in both cases. The pathogenicity of these mutations has been established in several mitochondria-related functional analyses in this study. Mitochondrial diseases with isolated renal symptoms are uncommon; however, this study indicates that mitochondrial respiratory chain complex III deficiency due to BCS1L mutations cause Fanconi syndrome with developmental disability as the primary indications.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Klootwijk ED, Reichold M, Unwin RJ, Kleta R, Warth R, Bockenhauer D. Renal Fanconi syndrome: taking a proximal look at the nephron. Nephrol Dial Transpl. 2015;30:1456–60.
Magen D, Berger L, Coady MJ, Ilivitzki A, Militianu D, Tieder M, et al. A loss-of-function mutation in NaPi-IIa and renal Fanconi’s syndrome. N Engl J Med. 2010;362:1102–9.
Klootwijk ED, Reichold M, Helip-Wooley A, Tolaymat A, Broeker C, Robinette SL, et al. Mistargeting of peroxisomal EHHADH and inherited renal Fanconi’s syndrome. N Engl J Med. 2014;370:129–38.
Santer R, Schneppenheim R, Dombrowski A, Götze H, Steinmann B, Schaub J. Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome. Nat Genet. 1997;17:324–6.
Hamilton AJ, Bingham C, McDonald TJ, Cook PR, Caswell RC, Weedon MN, et al. The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype. J Med Genet. 2014;51:165–9.
Reichold M, Klootwijk ED, Reinders J, Otto EA, Milani M, Broeker C, et al. Glycine amidinotransferase (GATM), renal Fanconi syndrome, and kidney failure. J Am Soc Nephrol. 2018;29:1849–58.
Niaudet P, Rötig A. Renal involvement in mitochondrial cytopathies. Pediatr Nephrol. 1996;10:368–73.
Govers LP, Toka HR, Hariri A, Walsh SB, Bockenhauer D. Mitochondrial DNA mutations in renal disease: an overview. Pediatr Nephrol. 2021;36:9–17.
Murayama K, Shimura M, Liu Z, Okazaki Y, Ohtake A. Recent topics: the diagnosis, molecular genesis, and treatment of mitochondrial diseases. J Hum Genet. 2019;64:113–25.
Kuwertz-Bröking E, Koch HG, Marquardt T, Rossi R, Helmchen U, Müller-Höcker J, et al. Renal Fanconi syndrome: first sign of partial respiratory chain complex IV deficiency. Pediatr Nephrol. 2000;14:495–8.
Morris AA, Taylor RW, Birch-Machin MA, Jackson MJ, Coulthard MG, Bindoff LA, et al. Neonatal Fanconi syndrome due to deficiency of complex III of the respiratory chain. Pediatr Nephrol. 1995;9:407–11.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.
Yatsuga S, Fujita Y, Ishii A, Fukumoto Y, Arahata H, Kakuma T, et al. Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders. Ann Neurol. 2015;78:814–23.
Kirby DM, Crawford M, Cleary MA, Dahl HH, Dennett X, Thorburn DR. Respiratory chain complex I deficiency: an underdiagnosed energy generation disorder. Neurology. 1999;52:1255–64.
Rahman S, Blok RB, Dahl HH, Danks DM, Kirby DM, Chow CW, et al. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol. 1996;39:343–51.
Bernier FP, Boneh A, Dennett X, Chow CW, Cleary MA, Thorburn DR. Diagnostic criteria for respiratory chain disorders in adults and children. Neurology. 2002;59:1406–11.
Van Coster R, Smet J, George E, De Meirleir L, Seneca S, Van Hove J, et al. Blue native polyacrylamide gel electrophoresis: a powerful tool in diagnosis of oxidative phosphorylation defects. Pediatr Res. 2001;50:658–65.
Dabbeni-Sala F, Di Santo S, Franceschini D, Skaper SD, Giusti P. Melatonin protects against 6-OHDA-induced neurotoxicity in rats: a role for mitochondrial complex I activity. FASEB J. 2001;15:164–70.
Calvo SE, Compton AG, Hershman SG, Lim SC, Lieber DS, Tucker EJ, et al. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Transl Med. 2012;4:118ra10.
Shigematsu Y, Hayashi R, Yoshida K, Shimizu A, Kubota M, Komori M, et al. Novel heterozygous deletion mutation c.821delC in the AAA domain of BCS1L underlies Björnstad syndrome. J Dermatol. 2017;44:e111–e12.
Cruciat CM, Hell K, Fölsch H, Neupert W, Stuart RA. Bcs1p, an AAA-family member, is a chaperone for the assembly of the cytochrome bc(1) complex. EMBO J. 1999;18:5226–33.
Jackson CB, Bauer MF, Schaller A, Kotzaeridou U, Ferrarini A, Hahn D, et al. A novel mutation in BCS1L associated with deafness, tubulopathy, growth retardation and microcephaly. Eur J Pediatr. 2016;175:517–25.
Ezgu F, Senaca S, Gunduz M, Tumer L, Hasanoglu A, Tiras U, et al. Severe renal tubulopathy in a newborn due to BCS1L gene mutation: effects of different treatment modalities on the clinical course. Gene. 2013;528:364–6.
Baker RA, Priestley JRC, Wilstermann AM, Reese KJ, Mark PR. Clinical spectrum of BCS1L Mitopathies and their underlying structural relationships. Am J Med Genet A. 2019;179:373–80.
Diomedi-Camassei F, Di Giandomenico S, Santorelli FM, Caridi G, Piemonte F, Montini G, et al. COQ2 nephropathy: a newly described inherited mitochondriopathy with primary renal involvement. J Am Soc Nephrol. 2007;18:2773–80.
Heeringa SF, Chernin G, Chaki M, Zhou W, Sloan AJ, Ji Z, et al. COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J Clin Invest. 2011;121:2013–24.
Ashraf S, Gee HY, Woerner S, Xie LX, Vega-Warner V, Lovric S, et al. ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J Clin Invest. 2013;123:5179–89.
Koga Y, Povalko N, Inoue E, Ishii A, Fujii K, Fujii T, et al. A new diagnostic indication device of a biomarker growth differentiation factor 15 for mitochondrial diseases: from laboratory to automated inspection. J Inherit Metab Dis. 2021;44:358–66.
Invernizzi F, D’Amato I, Jensen PB, Ravaglia S, Zeviani M, Tiranti V. Microscale oxygraphy reveals OXPHOS impairment in MRC mutant cells. Mitochondrion. 2012;12:328–35.
Ogawa E, Shimura M, Fushimi T, Tajika M, Ichimoto K, Matsunaga A, et al. Clinical validity of biochemical and molecular analysis in diagnosing Leigh syndrome: a study of 106 Japanese patients. J Inherit Metab Dis. 2017;40:685–93.
Arakawa C, Endo A, Kohira R, Fujita Y, Fuchigami T, Mugishima H, et al. Liver-specific mitochondrial respiratory chain complex I deficiency in fatal influenza encephalopathy. Brain Dev. 2012;34:115–7.
Funding
This study was supported by Grants-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (subject ID: 19K17297 to NS, 17H04189 to KI, 19K08726 to KN, and 18K07892 to YK). This study was also supported partly by the Japan Agency for Medical Research and Development, Grant/Award Numbers: JP17ek0109088 and JP19ek0109336 to YK.
Author information
Authors and Affiliations
Contributions
K-I K, NS, and KN: conception or design; K-I K, NS, KM, AO, and YK: data collection and analysis; K-I K and NS: data interpretation. HS, TU, KK, K-I Y, and HM: WES analysis and interpretation; K-I K, KN, SM, YI and YM: collection of patient samples and clinical information; K-I K and NS: drafting the article; TH, CN, TY, and KI: critical revision of the article. All authors approved the final version of the manuscript for publication.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Ethical approval
All procedures involving human participants were in accordance with the ethical standards of the Institutional Review Board of Kobe University Graduate School of Medicine (IRB approval number 301), the Kurume University Institutional Review Board (IRB approval number 273), the Kyushu University Institutional Review Board (IRB approval number 667-00), and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all individuals participating in this study.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Kanako, KI., Sakakibara, N., Murayama, K. et al. BCS1L mutations produce Fanconi syndrome with developmental disability. J Hum Genet 67, 143–148 (2022). https://doi.org/10.1038/s10038-021-00984-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s10038-021-00984-0