Missense Mutations in the<i>BCS1L</i>Gene as a Cause of the Björnstad Syndrome

Hinson, J. Travis; Fantin, Valeria R.; Schönberger, Jost; Breivik, Noralv; Siem, Geir; McDonough, Barbara; Sharma, Pankaj; Keogh, Ivan; Godinho, Ricardo; Santos, Felipe; Esparza, Alfonso; Nicolau, Yamileth; Selvaag, Edgar; Cohen, Bruce H.; Hoppel, Charles L.; Tranebjærg, Lisbeth; Eavey, Roland D.; Seidman, J. G.; Seidman, Christine E.

doi:10.1056/nejmoa055262

Cited by 190 publications

(190 citation statements)

References 29 publications

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“…Clinical presentations can include lactic acidosis, sensorineural loss, liver failure, LHON, developmental delay, cardiomyopathies and encephalopathy [80][81][82][83]. In addition, mutations in genes encoding CIII assembly factors have also been identified [84,85]. species production, resulting in a severe multiple systems condition [84] (Table 1).…”

Section: Oxphos Complex IIImentioning

confidence: 99%

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Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

2016

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SynopsisMitochondria provide the main source of energy to eukaryotic cells, oxidizing fats and sugars to generate ATP . Mitochondrial fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two metabolic pathways which are central to this process. Defects in these pathways can result in diseases of the brain, skeletal muscle, heart and liver, affecting approximately 1 in 5000 live births. There are no effective therapies for these disorders, with quality of life severely reduced for most patients. The pathology underlying many aspects of these diseases is not well understood; for example, it is not clear why some patients with primary FAO deficiencies exhibit secondary OXPHOS defects. However, recent findings suggest that physical interactions exist between FAO and OXPHOS proteins, and that these interactions are critical for both FAO and OXPHOS function. Here, we review our current understanding of the interactions between FAO and OXPHOS proteins and how defects in these two metabolic pathways contribute to mitochondrial disease pathogenesis.Key words: disease, mitochondria, protein complex assembly, protein interactions, supercomplex. MITOCHONDRIAL METABOLISMMitochondria occupy almost all human cell types and are involved in essential metabolic and cellular processes, including calcium and iron homoeostasis, apoptosis, innate immunity and haeme biosynthesis [1]. However, the primary function of mitochondria is the production of energy in the form of ATP [2][3][4]. ATP is the body's energy currency, playing vital roles in cell differentiation, growth and reproduction, thermogenesis and powering the contraction of muscles for movement [1]. In humans, ATP is produced by two different processes; through the breakdown of glucose or other sugars in Abbreviations: ACAD9, acyl-CoA dehydrogenase 9; BN-PAGE, blue native polyacrylamide gel electrophoresis; CACT, carnitine acylcarnitine translocase; CI, oxidative phosphorylation complex I (NADH: ubiquinone oxidoreductase, EC 1.6.5.3); CII, oxidative phosphorylation complex II (succinate: ubiquinone oxidoreductase, EC 1.3.5.1); CIII, oxidative phosphorylation complex III (ubiquinol: ferricytochrome c oxidoreductase, EC 1.10.2.2); CIV, oxidative phosphorylation complex IV (cytochrome c oxidase, EC 1.9.3.1); COPP , complex one phylogenetic profile; CPT1, carnitine O-palmitoyltransferase 1; CPT2, carnitine O-palmitoyltransferase 2; CV, OXPHOS complex V (FoF 1 -ATP synthetase, EC; 3.6.3.14); ECHS1, enoyl-CoA hydratase, short chain 1, mitochondrial; ECI1, enoyl-CoA delta isomerase, 1; ETF, electron transfer flavoprotein; ETFA, electron transfer flavoprotein alpha subunit; ETFB, electron transfer flavoprotein beta subunit; ETF-QO, electron transfer flavoprotein: ubiquinone oxidoreductase; FAD, flavin adenine dinucleotide; FADH 2 , reduced flavin adenine dinucleotide; FAO, fatty acid β-oxidation; H 2 O, water; HADH, hydroxyacyl-CoA dehydrogenase; KAT, 3-ketoacyl-CoA thiolase, mitochondrial; LCAD, long chain acyl-CoA dehydrogenase; LCEH, long chain enoyl-CoA hydra...

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Section: Oxphos Complex IIImentioning

confidence: 99%

“…In addition, mutations in genes encoding CIII assembly factors have also been identified [84,85]. species production, resulting in a severe multiple systems condition [84] (Table 1).…”

Section: Oxphos Complex IIImentioning

confidence: 99%

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

2016

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“…Regarding complex III enzyme deficiency, two studies analyzed the impact on ROS production of mutations in the BCS1L assembly factor, involved in the insertion of the catalytic Rieske Iron Sulphur Protein (RISP) into complex III (Cruciat et al, 1999;Hinson et al, 2007;Moran et al, 2010a). One of these studies revealed defective complex III enzyme activities and respirasome assembly defects that correlated with increased superoxide levels in isolated mitochondria of lymphocytes from patients with either complex III deficiency or Björnstad syndrome (Hinson et al, 2007).…”

Section: In Mitochondrial Disordersmentioning

confidence: 99%

“…One of these studies revealed defective complex III enzyme activities and respirasome assembly defects that correlated with increased superoxide levels in isolated mitochondria of lymphocytes from patients with either complex III deficiency or Björnstad syndrome (Hinson et al, 2007). The second study was performed with skin fibroblasts from six complex III-deficient patients with BCS1L mutations, which showed a marked correlation between the severity of the enzyme deficiencies and assembly defects of the RC complexes I, III and IV and raised H 2 O 2 levels, together with an unbalanced expression of the cellular antioxidant defenses (Moran et al, 2010a).…”

Section: In Mitochondrial Disordersmentioning

confidence: 99%

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Morán

Moreno-Lastres

Marín-Buera

et al. 2012

Free Radical Biology and Medicine

144

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For decades mitochondria have been considered static round shaped organelles in charge of energy production. On the contrary, they are highly dynamic cellular components that undergo continuous cycles of fusion and fission influenced, for instance, by oxidative stress, cellular energy requirements, or the cell cycle state. New important functions beyond energy production have been attributed to mitochondria, such as the regulation of cell survival due to their role in the modulation of apoptosis, autophagy and aging. Primary mitochondrial diseases due to mutations in genes involved in these new mitochondrial functions, and the implication of mitochondrial dysfunction in multifactorial human pathologies like cancer, Alzheimer's and Parkinson's diseases, or diabetes has been demonstrated. Therefore, mitochondria are set at a central point of the equilibrium between health and disease, and a better understanding of mitochondrial functions will open new fields to explore the role of these mitochondrial pathways in human pathologies. The present review will dissect the relationships between the activity and assembly defects of the mitochondrial respiratory chain, oxidative damage, and alterations in mitochondrial dynamics, with special focus at their implications in neurodegeneration.

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“…Systemic symptoms include hepatopathy and renal tubulopathy. Mutations in the complex III assembly factor BCS1L cause GRACILE syndrome (growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, early death) and Bjornstad syndrome (sensorineural hearing loss with pili torti) [40][41][42].…”

Section: Complex IIImentioning

confidence: 99%

Mitochondrial Disease in Childhood: Nuclear Encoded

2013

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Primary mitochondrial disorders are clinically and genetically heterogeneous, caused by an alteration(s) in either mitochondrial DNA or nuclear DNA, and affect the respiratory chain's ability to undergo oxidative phosphorylation, leading to decreased production of adenosine triphosphophate and subsequent energy failure. These disorders may present at any age, but children tend to have an acute onset of disease compared with subacute or slowly progressive presentation in adults. Varying organ involvement also contributes to the phenotypic spectrum seen in these disorders. The childhood presentation of primary mitochondrial disease is mainly due to nuclear DNA mutations, with mitochondrial DNA mutations being less frequent in childhood and more prominent in adulthood disease. The clinician should be aware of the pediatric presentation of mitochondrial disease and have an understanding of the myriad of nuclear genes responsible for these disorders. The nuclear genes can be best understood by utilizing a classification system of location and function within the mitochondria.

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Missense Mutations in theBCS1LGene as a Cause of the Björnstad Syndrome

Cited by 190 publications

References 29 publications

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Mitochondrial Disease in Childhood: Nuclear Encoded

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