Abstract: PO1361
BCS1L Mutations Produce Fanconi Syndrome with Developmental Disability
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - II
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Sakakibara, Nana, Kobe University Graduate School of Medicine, Kobe, Japan
- Nagai, Sadayuki, Kobe University Graduate School of Medicine, Kobe, Japan
- Aoto, Yuya, Kobe University Graduate School of Medicine, Kobe, Japan
- Nagano, China, Kobe University Graduate School of Medicine, Kobe, Japan
- Horinouchi, Tomoko, Kobe University Graduate School of Medicine, Kobe, Japan
- Yamamura, Tomohiko, Kobe University Graduate School of Medicine, Kobe, Japan
- Iijima, Kazumoto, Hyogo Prefectural Kobe Children’s Hospital, Kobe, Japan
- Nozu, Kandai, Kobe University Graduate School of Medicine, Kobe, Japan
Background
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.
Methods
We analyzed the patients clinically diagnosed with Fanconi syndrome of unknown cause. Patient-1 was a 3-year-old girl and Patient-2 was a 10-months-old boy. They were diagnosed with Fanconi syndrome based on renal tubular dysfunction, rickets, and elevated aspartate aminotransferase and alanine aminotransferase levels. They also had severe developmental disability and growth failure. Patient-1 had twin brothers who were diagnosed with Fanconi syndrome. GDF-15, a mitochondrial disease biomarker, was evaluated as an analysis of mitochondrial dysfunction. The following assays were also performed to confirm the pathogenicity of the novel mutations: oxygen consumption rate (OCR) of mitochondria, the activity of mitochondrial respiratory chain complexes.
Results
Whole-exome sequencing detected compound heterozygous BCS1L mutations, which cause mitochondrial respiratory chain complex III deficiency. In Patient-1, we identified missense mutation and frameshift mutation of BCS1L, c.268C>T, p.(Arg90Cys) and c.821del, p.(Pro274Argfs*26). These mutations have been reported previously. In Patient-2, we also identified novel missense mutations of BCS1L, c.167G>A, p.(Arg56Gln) and c.1195T>G, p.(Tyr399Asp).
The level of GDF-15 was elevated in both patients; 1025.5 pg/mL in Patient-1 and 1152.1 pg/mL in Patient-2 (normal: <707.4 pg/mL). In Patient-2 skin fibroblasts, the activities of mitochondrial respiratory chain complexes were normal, whereas the OCR was significantly lower than that in the control.
Conclusion
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 primally indications.