Respiratory chain complex III deficiency due to mutated BCS1L: a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model
Abstract Background Mitochondrial diseases due to defective respiratory chain complex III (CIII) are relatively uncommon. The assembly of the eleven-subunit CIII is completed by the insertion of the Rieske iron-sulfur protein, a process for which BCS1L protein is indispensable. Mutations in the BCS1...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-04-01
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| Series: | Orphanet Journal of Rare Diseases |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13023-017-0624-2 |
| _version_ | 1819000664190091264 |
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| author | Saara Tegelberg Nikica Tomašić Jukka Kallijärvi Janne Purhonen Eskil Elmér Eva Lindberg David Gisselsson Nord Maria Soller Nicole Lesko Anna Wedell Helene Bruhn Christoph Freyer Henrik Stranneheim Rolf Wibom Inger Nennesmo Anna Wredenberg Erik A. Eklund Vineta Fellman |
| author_facet | Saara Tegelberg Nikica Tomašić Jukka Kallijärvi Janne Purhonen Eskil Elmér Eva Lindberg David Gisselsson Nord Maria Soller Nicole Lesko Anna Wedell Helene Bruhn Christoph Freyer Henrik Stranneheim Rolf Wibom Inger Nennesmo Anna Wredenberg Erik A. Eklund Vineta Fellman |
| author_sort | Saara Tegelberg |
| collection | DOAJ |
| description | Abstract Background Mitochondrial diseases due to defective respiratory chain complex III (CIII) are relatively uncommon. The assembly of the eleven-subunit CIII is completed by the insertion of the Rieske iron-sulfur protein, a process for which BCS1L protein is indispensable. Mutations in the BCS1L gene constitute the most common diagnosed cause of CIII deficiency, and the phenotypic spectrum arising from mutations in this gene is wide. Results A case of CIII deficiency was investigated in depth to assess respiratory chain function and assembly, and brain, skeletal muscle and liver histology. Exome sequencing was performed to search for the causative mutation(s). The patient’s platelets and muscle mitochondria showed respiration defects and defective assembly of CIII was detected in fibroblast mitochondria. The patient was compound heterozygous for two novel mutations in BCS1L, c.306A > T and c.399delA. In the cerebral cortex a specific pattern of astrogliosis and widespread loss of microglia was observed. Further analysis showed loss of Kupffer cells in the liver. These changes were not found in infants suffering from GRACILE syndrome, the most severe BCS1L-related disorder causing early postnatal mortality, but were partially corroborated in a knock-in mouse model of BCS1L deficiency. Conclusions We describe two novel compound heterozygous mutations in BCS1L causing CIII deficiency. The pathogenicity of one of the mutations was unexpected and points to the importance of combining next generation sequencing with a biochemical approach when investigating these patients. We further show novel manifestations in brain, skeletal muscle and liver, including abnormality in specialized resident macrophages (microglia and Kupffer cells). These novel phenotypes forward our understanding of CIII deficiencies caused by BCS1L mutations. |
| first_indexed | 2024-12-20T22:36:54Z |
| format | Article |
| id | doaj.art-4f5b4fca633f4964a3749feb2ec9be5e |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-12-20T22:36:54Z |
| publishDate | 2017-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-4f5b4fca633f4964a3749feb2ec9be5e2022-12-21T19:24:34ZengBMCOrphanet Journal of Rare Diseases1750-11722017-04-0112111410.1186/s13023-017-0624-2Respiratory chain complex III deficiency due to mutated BCS1L: a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse modelSaara Tegelberg0Nikica Tomašić1Jukka Kallijärvi2Janne Purhonen3Eskil Elmér4Eva Lindberg5David Gisselsson Nord6Maria Soller7Nicole Lesko8Anna Wedell9Helene Bruhn10Christoph Freyer11Henrik Stranneheim12Rolf Wibom13Inger Nennesmo14Anna Wredenberg15Erik A. Eklund16Vineta Fellman17Division of Pediatrics, Department of Clinical Sciences, Lund UniversityDivision of Pediatrics, Department of Clinical Sciences, Lund UniversityFolkhälsan Research CenterFolkhälsan Research CenterMitochondrial Medicine, Department of Clinical Sciences, Lund UniversityDepartment of Pathology, Regional Laboratories, Region SkåneDivision of Clinical Genetics, Department of Laboratory Medicine, Lund UniversityDivision of Clinical Genetics, Department of Laboratory Medicine, Lund UniversityCentre for inherited Metabolic Diseases, Karolinska University HospitalCentre for inherited Metabolic Diseases, Karolinska University HospitalCentre for inherited Metabolic Diseases, Karolinska University HospitalCentre for inherited Metabolic Diseases, Karolinska University HospitalCentre for inherited Metabolic Diseases, Karolinska University HospitalCentre for inherited Metabolic Diseases, Karolinska University HospitalDepartment of Pathology, Karolinska University HospitalCentre for inherited Metabolic Diseases, Karolinska University HospitalDivision of Pediatrics, Department of Clinical Sciences, Lund UniversityDivision of Pediatrics, Department of Clinical Sciences, Lund UniversityAbstract Background Mitochondrial diseases due to defective respiratory chain complex III (CIII) are relatively uncommon. The assembly of the eleven-subunit CIII is completed by the insertion of the Rieske iron-sulfur protein, a process for which BCS1L protein is indispensable. Mutations in the BCS1L gene constitute the most common diagnosed cause of CIII deficiency, and the phenotypic spectrum arising from mutations in this gene is wide. Results A case of CIII deficiency was investigated in depth to assess respiratory chain function and assembly, and brain, skeletal muscle and liver histology. Exome sequencing was performed to search for the causative mutation(s). The patient’s platelets and muscle mitochondria showed respiration defects and defective assembly of CIII was detected in fibroblast mitochondria. The patient was compound heterozygous for two novel mutations in BCS1L, c.306A > T and c.399delA. In the cerebral cortex a specific pattern of astrogliosis and widespread loss of microglia was observed. Further analysis showed loss of Kupffer cells in the liver. These changes were not found in infants suffering from GRACILE syndrome, the most severe BCS1L-related disorder causing early postnatal mortality, but were partially corroborated in a knock-in mouse model of BCS1L deficiency. Conclusions We describe two novel compound heterozygous mutations in BCS1L causing CIII deficiency. The pathogenicity of one of the mutations was unexpected and points to the importance of combining next generation sequencing with a biochemical approach when investigating these patients. We further show novel manifestations in brain, skeletal muscle and liver, including abnormality in specialized resident macrophages (microglia and Kupffer cells). These novel phenotypes forward our understanding of CIII deficiencies caused by BCS1L mutations.http://link.springer.com/article/10.1186/s13023-017-0624-2Mitochondrial disorderRespiratory chainRespirometryAssembly factorsBlue native gel electrophoresisEncephalopathy |
| spellingShingle | Saara Tegelberg Nikica Tomašić Jukka Kallijärvi Janne Purhonen Eskil Elmér Eva Lindberg David Gisselsson Nord Maria Soller Nicole Lesko Anna Wedell Helene Bruhn Christoph Freyer Henrik Stranneheim Rolf Wibom Inger Nennesmo Anna Wredenberg Erik A. Eklund Vineta Fellman Respiratory chain complex III deficiency due to mutated BCS1L: a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model Orphanet Journal of Rare Diseases Mitochondrial disorder Respiratory chain Respirometry Assembly factors Blue native gel electrophoresis Encephalopathy |
| title | Respiratory chain complex III deficiency due to mutated BCS1L: a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model |
| title_full | Respiratory chain complex III deficiency due to mutated BCS1L: a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model |
| title_fullStr | Respiratory chain complex III deficiency due to mutated BCS1L: a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model |
| title_full_unstemmed | Respiratory chain complex III deficiency due to mutated BCS1L: a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model |
| title_short | Respiratory chain complex III deficiency due to mutated BCS1L: a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model |
| title_sort | respiratory chain complex iii deficiency due to mutated bcs1l a novel phenotype with encephalomyopathy partially phenocopied in a bcs1l mutant mouse model |
| topic | Mitochondrial disorder Respiratory chain Respirometry Assembly factors Blue native gel electrophoresis Encephalopathy |
| url | http://link.springer.com/article/10.1186/s13023-017-0624-2 |
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