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BCS1L mutations produce Fanconi syndrome with developmental disability


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.

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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.

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Authors and Affiliations



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.

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Correspondence to Nana Sakakibara.

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The authors declare no competing interests.

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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.

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Kanako, KI., Sakakibara, N., Murayama, K. et al. BCS1L mutations produce Fanconi syndrome with developmental disability. J Hum Genet 67, 143–148 (2022).

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