Respiratory chain complex III deficiency due to mutated BCS1L : a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model

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Tegelberg , S , Tomasic , N , Kallijärvi , J , Purhonen , J , Elmer , E , Lindberg , E , Nord , D G , Soller , M , Lesko , N , Wedell , A , Bruhn , H , Freyer , C , Stranneheim , H , Wibom , R , Nennesmo , I , Wredenberg , A , Eklund , E A & Fellman , V 2017 , ' 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 , vol. 12 , 73 . https://doi.org/10.1186/s13023-017-0624-2

Title: Respiratory chain complex III deficiency due to mutated BCS1L : a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model
Author: Tegelberg, Saara; Tomasic, Nikica; Kallijärvi, Jukka; Purhonen, Janne; Elmer, Eskil; Lindberg, Eva; Nord, David Gisselsson; Soller, Maria; Lesko, Nicole; Wedell, Anna; Bruhn, Helene; Freyer, Christoph; Stranneheim, Henrik; Wibom, Rolf; Nennesmo, Inger; Wredenberg, Anna; Eklund, Erik A.; Fellman, Vineta
Contributor organization: University of Helsinki
Clinicum
HUS Children and Adolescents
Date: 2017-04-20
Language: eng
Number of pages: 14
Belongs to series: Orphanet journal of rare diseases
ISSN: 1750-1172
DOI: https://doi.org/10.1186/s13023-017-0624-2
URI: http://hdl.handle.net/10138/299254
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.
Subject: Mitochondrial disorder
Respiratory chain
Respirometry
Assembly factors
Blue native gel electrophoresis
Encephalopathy
Hepatopathy
Microglia
Barrel cortex
LETHAL METABOLIC-DISORDER
FETAL-GROWTH-RETARDATION
IRON-OVERLOAD
GRACILE SYNDROME
MITOCHONDRIAL DISEASE
SUBVENTRICULAR ZONE
LACTIC-ACIDOSIS
NEUROPATHOLOGY
NEUROGENESIS
MUTATIONS
3111 Biomedicine
1184 Genetics, developmental biology, physiology
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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