Original Article
Missense Mutations in the BCS1L Gene as a Cause of the Björnstad Syndrome
N Engl J Med 2007; 356:809-819February 22, 2007
- Abstract
Background
The Björnstad syndrome, an autosomal recessive disorder associated with sensorineural hearing loss and pili torti, is caused by mutation of a previously unidentified gene on chromosome 2q34–36.
Methods
Refined genetic mapping and DNA sequencing of 44 genes between D2S2210 and D2S2244 revealed BCS1L mutations. Functional analyses elucidated how BCS1L mutations cause the Björnstad syndrome.
Results
BCS1L encodes a member of the AAA family of ATPases that is necessary for the assembly of complex III in the mitochondria. In addition to the Björnstad syndrome, BCS1L mutations cause complex III deficiency and the GRACILE syndrome, which in neonates are lethal conditions that have multisystem and neurologic manifestations typifying severe mitochondrial disorders. Patients with the Björnstad syndrome have mutations that alter residues involved in protein–protein interactions, whereas mutations in patients with complex III deficiency alter ATP-binding residues, as deduced from the crystal structure of a related AAA-family ATPase. Biochemical studies provided evidence to support this model: complex III deficiency mutations prevented ATP-dependent assembly of BCS1L-associated complexes. All mutant BCS1L proteins disrupted the assembly of complex III, reduced the activity of the mitochondrial electron-transport chain, and increased the production of reactive oxygen species. However, only mutations associated with complex III deficiency increased mitochondrial content, which further increased the production of reactive oxygen species.
Conclusions
BCS1L mutations cause disease phenotypes ranging from highly restricted pili torti and sensorineural hearing loss (the Björnstad syndrome) to profound multisystem organ failure (complex III deficiency and the GRACILE syndrome). All BCS1L mutations disrupted the assembly of mitochondrial respirasomes (the basic unit for respiration in human mitochondria), but the clinical expression of the mutations was correlated with the production of reactive oxygen species. Mutations that cause the Björnstad syndrome illustrate the exquisite sensitivity of ear and hair tissues to mitochondrial function, particularly to the production of reactive oxygen species.
Media in This Article
Figure 1
BCS1L Mutations That Cause the Björnstad Syndrome.Figure 2
Human BCS1L Mutations.Article Activity
- Article
The Björnstad syndrome is an autosomal recessive condition characterized by sensorineural hearing loss and pili torti.1,2 The hearing loss in the Björnstad syndrome is congenital and of variable severity. Pili torti (twisted hairs), a condition in which the hair shafts are flattened at irregular intervals and twisted 180 degrees from the normal axis, making the hair extremely brittle,3 is usually recognized early in childhood. We previously mapped the gene responsible for the Björnstad syndrome to chromosome 2q34–36.4 Here we show that mutations in the BCS1L gene cause the Björnstad syndrome by disrupting the assembly of mitochondrial respirasomes, which are the basic unit for respiration in human mitochondria.
BCS1L, a 419-amino-acid chaperone protein, is a member of the family called AAA, an acronym for ATPases associated with various cellular activities.5,6 The AAA-family ATPases mediate the folding, unfolding, assembly, and degradation of proteins.7,8 Found within the inner mitochondrial membrane, BCS1L is presumed to facilitate insertion of Rieske Fe/S protein into precursors to complex III5 during assembly of the respiratory chain. Complex III then becomes assembled with complexes IV and I into a respirasome supercomplex that facilitates the electron transfer required for the synthesis of ATP.9,10
BCS1L mutations have previously been reported to cause complex III deficiency1 (manifested by neonatal tubulopathy, encephalopathy, and liver failure; Online Mendelian Inheritance in Man [OMIM] number 606104) and the more severe disorder of intrauterine growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death, termed the GRACILE syndrome (OMIM number 603358).11,12 The clinical findings of these profoundly severe multisystem disorders are more typical of gene mutations that disrupt the mitochondrial respiratory-chain complex than are the highly restricted clinical findings associated with the Björnstad syndrome.
To understand how BCS1L mutations cause such widely different clinical phenotypes, we considered the locations of defects on the BCS1L protein structure and compared the function of mutant BCS1L in yeast and in human lymphocytes. These studies showed that BCS1L mutations altered assembly of the mitochondrial respirasome, reduced activity of the electron transport chain, and increased the production of reactive oxygen species. The production of reactive oxygen species was correlated with the clinical severity of different BCS1L mutations. These data indicate that in addition to mitochondrial heteroplasmy and variable energy requirements of tissues, tissue-specific sensitivities to reactive oxygen species contribute to the variability of the manifestations of mitochondrial defects.
Methods
DNA Sequencing and Mutation Analysis
We amplified genomic DNA, prepared as previously described,4 using primers flanking exon–intron gene boundaries, and we sequenced the DNA using the ABI BigDye method in an Applied Biosystems Prism 3700 DNA Analyzer. Sequence variants were confirmed by restriction-enzyme digestion, and polymorphisms were identified in National Institutes of Health (NIH)13 and Celera14 databases.
Immunohistochemistry
Paraffin-embedded sections of human scalp and mouse inner-ear tissue were prepared for antigen retrieval as previously described.15 Scalp sections were reacted with antibodies to BCS1L (Proteinech Group) and to core protein 1 (Molecular Probes), followed by antigen detection with a fluorescein-conjugated biotin–streptavidin system (Vector Laboratories). Binding of antibody to murine inner-ear sections was detected with alkaline phosphatase and NBT/BCIP substrate (Roche). Fluorescent images were captured with a confocal microscope (Leica Microsystems) and processed with NIH Image and Adobe Photoshop software.
Complementation Studies with Yeast
Mutations were introduced into human BCS1L by means of a site-directed mutagenesis kit (QuikChange, Stratagene) that used overlapping primers containing the desired mutation that were introduced into the pMGL3 vector.16 Constructs were transfected into Bcs1-deficient yeast (aW303ΔBcs1) and grown on rich (YPDextrose) or mitochondria-selective (YPEthanol/Glycerol) media at 30°C for 4 days. The size and growth of the colony (measured by log-phase doubling times of cultures; initial concentration, 1×105 cells per well) were compared between wild-type (W303-1A) yeast and aW303ΔBcs1 transfected with wild-type yeast Bcs1, wild-type human BCS1L, empty vector (pMGL3), or human mutant BCS1L.
Mitochondrial Extraction, Analysis, and Content
Actively growing transformed lymphocytes were washed, and a crude mitochondrial fraction was extracted as previously described.17 Mitochondrial preparations, isolated in the presence or absence of magnesium plus either ATP or γS-ATP, were solubilized in 0.75 M ε-aminocaproic acid, 50 mM Bis-Tris (pH 7.0), and 5 mg of digitonin per milliliter (all from Sigma). The complexes underwent blue-native polyacrylamide-gel electrophoresis as previously described.9 Western blots of protein complexes were probed with antibodies to BCS1L, core protein 1, and Rieske Fe/S proteins. Before undergoing Western blot analyses with Rieske Fe/S protein antibody (Invitrogen Molecular Probes), samples were run on a second dimension of sodium dodecyl sulfate–polyacrylamide-gel electrophoresis. Mitochondrial content was assessed by staining transformed lymphocytes with MitoTracker Green FM and hydroethidium to normalize for cell number (Invitrogen Molecular Probes).
Electron-Transport-Chain Activity
The rate of reduction of resazurin dye, which was dependent on the electron-transport chain, was measured by spectrophotometry of lymphocytes treated with the F1-ATP synthase inhibitor oligomycin as previously described.18 The mean (±SE) values from at least three assays are reported.
Production of Reactive Oxygen Species
Production of reactive oxygen species was assessed in isolated mitochondria treated with complex-specific substrates, with inhibitors and without inhibitors, and analyzed with the use of the hydrogen peroxide–sensitive dye Amplex Red (Invitrogen Molecular Probes).19 The substrates were glutamate and malate for complex I and succinate for complex III. The inhibitors were rotenone for complex I and antimycin A plus rotenone for complex III (Sigma-Aldrich). Superoxide was monitored as hydrogen peroxide after the addition of superoxide dismutase (Sigma-Aldrich) to mitochondrial isolates. The values were controlled for mitochondrial content and normalized to cell number. The mean values from at least three assays are reported.
Results
Gene Sequencing
We previously identified the locus of the autosomal recessive gene for the Björnstad syndrome1,2 on chromosome 2q34–36.4 Fine mapping in a consanguineous family with the Björnstad syndrome (BS1) (Figure 1AFigure 1
BCS1L Mutations That Cause the Björnstad Syndrome.) narrowed the critical disease region to a 2-megabase region between D2S2210 and D2S2244 that contains 47 genes (Figure 1B). DNA sequences encoding 44 genes were determined in BS1 family members. After previously reported polymorphisms had been excluded,13,14 one sequence variant remained in BCS1L. The single-nucleotide variant in BCS1L substituted a histidine for an arginine (R183H) and was absent in 300 normal chromosomes.BCS1L was then sequenced in four unrelated probands with the Björnstad syndrome (BS2 to BS5) (Figure 2AFigure 2
Human BCS1L Mutations.). Five additional BCS1L sequence variants were identified: one affected splice-site sequences, three encoded missense residues, and one encoded premature termination. Three probands of Norwegian ancestry carried at least one BCS1L R306H allele. To exclude the possibility that this allele reflected a population-specific polymorphism, 120 chromosomes from unaffected, unrelated Norwegians were analyzed; the R306H variant was absent in all. All other BCS1L sequence variants were absent in 300 chromosomes from normal, unrelated persons. Each BCS1L sequence variant altered an evolutionarily conserved residue (Figure 2C). We concluded that BCS1L mutations cause the Björnstad syndrome.Mutation Analysis
We also identified two BCS1L mutations (G35R and R184C, designated CIII) in a 4-year-old child who had clinical manifestations of the Björnstad syndrome as well as growth retardation, developmental delay, and profound hypotonia. These multiorgan phenotypes resembled those of mild complex III deficiency.1,11,12 Spectrophotometric analysis of enzymatic activities of electron-transport complexes21-23 from skeletal muscle showed that complex III activity was reduced to 15% of normal. Hearing loss, but not pili torti, occurs in complex III deficiency12; neither is a typical feature of the GRACILE syndrome, perhaps because recognition of the syndrome is hindered by complex systemic manifestations and early death.
We considered how the type and location of BCS1L mutations contributed to the different human phenotypes. BCS1L has two functional domains (Figure 2B): a sorting sequence (amino acids 1 through 89) that facilitates translocation and insertion into the mitochondrial inner membrane,24,25 and the domain of the AAA-family ATPase (residues 220 through 399).
Two mutations associated with the Björnstad syndrome and one mutation associated with complex III deficiency and the GRACILE syndrome encoded truncated BCS1L peptides; these mutations are presumed to be functionally null alleles (Figure 2B). Two other reported mutations associated with complex III deficiency and the GRACILE syndrome, as well as the CIII mutation, affected sorting sequences; by preventing BCS1L from reaching the mitochondrial inner membrane, these mutations may also be functionally null alleles. Each patient with the Björnstad syndrome carried at least one allele that was predicted to have partial function.
We located five BCS1L mutations within the AAA domain on the three-dimensional structure (Figure 2D) of Escherichia coli RuvB,20 which has the highest sequence homology to BCS1L of all AAA domains.26 Three mutations associated with complex III deficiency and the GRACILE syndrome, including a missense mutation (S277N) in the Walker B domain,27 altered residues that directly interact with magnesium or ATP, a finding that implied that these defects impair nucleotide binding or hydrolysis. In contrast, mutations at residues 302 and 306 in patients with the Björnstad syndrome altered an exterior face of the AAA domain, a location that suggested that these defects affect interactions between BCS1L and other proteins.
Immunohistochemical Analysis
We examined the expression of complex III by means of immunohistochemical analysis using antibodies specific to BCS1L and core protein 1, a component of complex III. Concentric layers of mitochondria-rich cells with abundant amounts of BCS1L and core protein 1 were most prominent at the dermal papilla (Figure 3AFigure 3
BCS1L Expression in Hair and Ear Mitochondria.) but also surrounded the hair shaft throughout the length of the follicle in sections of skin from the normal human scalp. In the mouse inner ear, antibodies to BCS1L and core protein 1 produced strong immunostaining in the hair cells and the stria vascularis (Figure 3B). Although the tissues in which these proteins were expressed are those that are involved in the Björnstad syndrome, BCS1L was also highly expressed in heart and brain tissues (data not shown).Mitochondrial Extraction
Because of the location of the mutations associated with the Björnstad syndrome and the ATPase activity of BCS1L, we examined whether mutations affected ATP-dependent protein–protein interactions. BCS1L-associated complexes were extracted with ATP or with γS-ATP, a nonhydrolyzable ATP analog, and analyzed by electrophoresis and Western blotting. In normal mitochondria, BCS1L antibody identified three complexes (Figure 4AFigure 4
Supercomplex Intermediates Found in Mitochondrial Extracts from Patients with Normal Lymphocytes (WT), Lymphocytes with Björnstad Syndrome Mutations (BS), and Lymphocytes with CIII Mutations.). The smallest species had a molecular weight of approximately 240 kD, a size consistent with a hexameric ring of BCS1L monomers (40 kD) (Figure 4C), the multimeric structure recognized in other AAA-family ATPases.28 No BCS1L mutations disrupted this structure.In normal mitochondria prepared with either hydrolyzable ATP or nonhydrolyzable γS-ATP, BCS1L antibody also labeled two complexes with higher molecular weights that were designated BCS1LH1 (approximately 400 kD) and BCS1LH2 (approximately 450 kD). Because both species were missing from extracts of mitochondria with the CIII mutation, these mutations prevented the formation of protein species that required ATP binding and hydrolysis (Figure 4C).
Mitochondrial extracts from patients with the Björnstad syndrome had abnormal ratios of BCS1LH1 and BCS1LH2 (Figure 4A). Because ATP regulates the chaperone activity of AAA-family ATPases28 and promotes dissociation of BCS1L from complex III,5 the mutations associated with the Björnstad syndrome may alter the ATP-dependent equilibrium between BCS1L within a hexameric ring or in BCS1LH1 and BCS1LH2 (Figure 4C). The consequence of these altered levels was the diminished assembly of complex III and the accumulation of unassembled Rieske Fe/S protein.
To examine whether different BCS1L mutations affected assembly of the respirasome, a molecular supercomplex, mitochondrial complexes were fractionated by electrophoresis and probed with antibodies (Figure 3B). Although all extracts contained a fully formed respirasome — (CIII)2(CIV)n(CI)n — the levels and mobility of intermediate species of respirasome differed among extracts from normal mitochondria, mitochondria from patients with the Björnstad syndrome, and mitochondria from patients with the CIII mutation. Normal mitochondrial extracts had prominent complex III dimers that contained Rieske Fe/S protein (denoted [CIII]2). In contrast, smaller complex III species without Rieske Fe/S protein (denoted [apoCIII]2) accumulated in mitochondrial extracts from BCS1L mutant lymphocytes. Intermediate respirasome complexes containing complex III and complex IV multimers were most prominent in extracts from CIII lymphocytes; lesser amounts were also found in extracts from patients with the Björnstad syndrome. No intermediate supercomplex species from mutant extracts were labeled by antibody to Rieske Fe/S protein (data not shown), a result indicating that mutant extracts accumulated (apoCIII)2(CIV)n intermediates without Rieske Fe/S protein. This conclusion was supported by the abundant accumulation of unassembled Rieske Fe/S protein in mitochondrial extracts from lymphocytes of patients with the Björnstad syndrome or with the CIII mutation, but not in extracts from normal controls (Figure 4B, bottom).
Complementation Studies with Yeast
To assess the functional consequences of human BCS1L mutations, we performed yeast complementation studies. Yeast lacking Bcs1, the BCS1L homologue,5 fail to incorporate Rieske Fe/S protein into complex III and do not grow on media that require respiratory-chain metabolism.6 This deficiency is complemented by normal human BCS1L 29 but not by BCS1L from patients with mutations associated with complex III deficiency or the GRACILE syndrome.12,30 We examined the growth of Bcs1-deficient yeast transfected with mutations causing the Björnstad syndrome and other BCS1L mutations (Figure 5AFigure 5
Functional Consequences of BCS1L Mutations in the Björnstad Syndrome and Complex III Deficiency.). Normal BCS1L supported yeast growth, but BCS1L with Björnstad syndrome mutations, the CIII mutation, and mutations associated with other complex III deficiencies attenuated growth on selective media to about the same degree. Although these data confirmed that mutations associated with the Björnstad syndrome cause mitochondrial dysfunction, they did not suggest why different mutations resulted in distinct clinical phenotypes.Electron-Transport-Chain Activity
We examined the functional consequences of BCS1L mutations for electron-transport-chain activity in lymphocyte mitochondria (Figure 5B). Normal electron-transport-chain activity was reduced in mitochondria from patients with the Björnstad syndrome (to 62% of normal, P=0.07) and in mitochondria with the CIII mutation (to 50% of normal, P=0.01). Reduced electron-transport-chain activity did not reflect mitochondrial content. Lymphocytes with the CIII mutation had 16% more mitochondria per cell than lymphocytes from patients with the Björnstad syndrome or normal lymphocytes (P=0.02).
Production of Reactive Oxygen Species
We assessed the production of reactive oxygen species from complexes I and III.31 In comparison with the amount of superoxide produced by normal lymphocyte mitochondria, the amount of superoxide produced by complex III activity was reduced by 61% in mitochondria from patients with the Björnstad syndrome (P=0.01) and by 68% in mitochondria from patients with the CIII mutation (P=0.02); the amounts of these reductions paralleled diminished electron-transport-chain activities. Complex I produces negligible superoxide in the normal respirasome,32 but complex I in mitochondria with mutations causing the Björnstad syndrome produced 30 times as much superoxide as normal (P=0.01) (Figure 5C). The amount of superoxide produced by complex I in mitochondria with the CIII mutation was still higher (50 times as much as normal, P=0.01) and was significantly greater than that produced by mitochondria with mutations causing the Björnstad syndrome (P=0.04).
Discussion
We have shown that recessive BCS1L mutations cause sensorineural hearing loss and pili torti in the Björnstad syndrome. Biochemical and functional studies of mutant BCS1L showed that this chaperone protein has essential roles in the assembly of complex III and the respirasome. Mutations associated with the Björnstad syndrome and CIII mutations in BCS1L resulted in the accumulation of mitochondrial respiratory intermediates that lacked Rieske Fe/S protein (Figure 4) and decreased electron-transport-chain activity. CIII mutations also increased mitochondrial content. Although all BCS1L mutations increased the production of reactive oxygen species, the amount of the increase was specific to the mutation and the disease.
The severity of the medical manifestations of BCS1L mutations was inversely correlated with the amounts of the high-molecular-weight mitochondrial complexes BCS1LH1 and BCS1LH2. These ATP-dependent complexes were missing in mitochondria with the CIII mutation, which confirmed structural predictions that these clinically severe BCS1L mutations impaired ATP binding or hydrolysis. In contrast, mutations causing the Björnstad syndrome only altered the normal ratios of high-molecular-weight BCS1L complexes, a finding consistent with the location of these mutations in residues on the external chaperone surface where protein–protein interactions may occur. Although we could not identify core protein 1, a component of complex III, in either BCS1LH1 or BCS1LH2, we hypothesize that these species may represent precursors of BCS1L or complex III, BCS1L hexamer conformations, or BCS1L bound to unidentified chaperones of complex III assembly. Nonetheless, the consequence of all BCS1L mutations was accumulation of complex III precursors that lacked the Rieske Fe/S protein. Remarkably, the assembly of respirasomes continued despite diminished chaperone activities of BCS1L, albeit with the accumulation of atypical intermediates such as (apoCIII)2(CIV)n.
Because unassembled respirasome complexes and free Rieske Fe/S protein occurred with all BCS1L mutations, these are unlikely to be major determinants of clinically disparate diseases. Furthermore, electron-transport-chain activity, as assessed indirectly by complementation analysis in yeast or in mitochondria from mutant lymphocytes, differed only moderately between mitochondria with mutations causing the Björnstad syndrome and mitochondria with CIII mutations. However, only CIII mutations led to a compensatory increase in the mitochondrial content of lymphocytes, which probably reflects a more severe electron-transport-chain defect.
An untoward effect of inadequate electron-transport-chain activity and increased mitochondrial content was increased production of reactive oxygen species. We found that all BCS1L mutations reduced complex III–mediated production of superoxide, which reflected diminished assembly of complex III due to impaired insertion of Rieske Fe/S protein; this model is supported by studies that directly implicate Rieske Fe/S protein in the production of reactive oxygen species.33 In contrast, production of superoxide by complex I was strikingly higher in mitochondria with CIII mutations than in those with mutations associated with Björnstad syndrome (P=0.04) (Figure 5). Whether increased production of superoxide by complex I reflected increased electron-transport-chain activity upstream of complex III (potentially further augmented by increased mitochondrial content in CIII mutations), toxic effects of abnormal respirasomes, or changes in chaperone activity, the degree to which BCS1L mutations increased the production of reactive oxygen species predicted disease phenotype.
We conclude that the BCS1L mutations that affect ATP binding or hydrolysis and severely disrupt complex III assembly cause disease by attenuating electron-transport-chain activity and markedly increasing the production of reactive oxygen species. Despite increased mitochondrial content, these mutations result in the multisystem organ failure that characterizes complex III deficiency and the GRACILE syndrome.
We suggest that the BCS1L mutations responsible for the highly restricted phenotype of the Björnstad syndrome increase the production of reactive oxygen species by complex I, which leads to oxidative stress in both the inner ear and the hair follicle. Current models of the effects of aminoglycoside antibiotics and excessive noise on hearing support a critical role for increased levels of reactive oxygen species in ototoxicity.34 We presume that hair-follicle cells that divide rapidly may also be particularly susceptible to increased levels of reactive oxygen species or to other respiratory-chain defects in patients with the Björnstad syndrome. We also note that mitochondrial disease is often manifested by a variety of hair abnormalities.18 Furthermore, we speculate that the remarkable tissue-specific manifestations of mutations leading to the Björnstad syndrome may hint at a shared mechanism for age-related hair abnormalities and hearing loss, since aging, like the BCS1L mutations associated with the Björnstad syndrome, increases the levels of reactive oxygen species.31
Supported by grants from the Howard Hughes Medical Institute and the National Institutes of Health.
No potential conflict of interest relevant to this article was reported.
Drs. J.G. Seidman and C.E. Seidman contributed equally to this article.
This work is dedicated to the memory of our colleague Alfonso Esparza.
We thank the patients and family members for their participation, M.A. Flores and R.M. Caldera for clinical assistance, Alexander Tzagoloff for providing plasmids and yeast strains, and Fred Winston and Lisa Laprade for technical assistance.
Source Information
From Harvard Medical School, Boston (J.T.H., V.R.F., J.S., B.M., I.K., A.E., Y.N., R.D.E., J.G.S., C.E.S.); the Howard Hughes Medical Institute, Boston (J.T.H., J.S., J.G.S., C.E.S.); University Hospital Würzburg and Institute of Clinical Biochemistry and Pathobiochemistry — both in Würzburg, Germany (J.S.); Aalesund Hospital, Norway (N.B., G.S.); Hammersmith Hospitals and Imperial College, London (P.S.); the Massachusetts Eye and Ear Infirmary, Boston (I.K., A.E., Y.N., R.D.E.); Instituto de Ciências Biológias e da Saúde, Pontifícia Universidade Cathólica de Minas Gerais, Belo Horizonte, Brazil (R.G.); University of Washington, Seattle (F.S.); H:S Bispebjerg Hospital, Copenhagen (E.S., L.T.); the Brain Tumor Institute, Cleveland Clinic, Cleveland (B.H.C.); Louis Stokes Veterans Affairs Medical Center, Cleveland (C.L.H.); and Institute of Medical Biochemistry and Genetics, University of Copenhagen, Copenhagen, and University Hospital of Tromsø, Tromsø, Norway (L.T.).
Address reprint requests to Dr. C.E. Seidman at the Department of Genetics, Harvard Medical School, Room 256 NRB, 77 Ave. Louis Pasteur, Boston, MA 02115, or at cseidman@genetics.med.harvard.edu.
- References
References
1
Online Mendelian Inheritance in Man (OMIM). McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University, NCBI, NLM, 2005. (Accessed January 26, 2007, at http://www.ncbi.nlm.nih.gov/omim/.)
2
Selvaag E . Pili torti and sensorineural hearing loss: a follow-up of Bjornstad's original patients and a review of the literature. Eur J Dermatol 2000;10:91-97
Web of Science | Medline3
Ronchese F . Twisted hairs (pili torti). Arch Dermatol Syphiol 1932;26:98-109
CrossRef | Web of Science4
Lubianca Neto JF ,Lu L ,Eavey RD , et al. The Bjornstad syndrome (sensorineural hearing loss and pili torti) disease gene maps to chromosome 2q34-36. Am J Hum Genet 1998;62:1107-1112
CrossRef | Web of Science | Medline5
Cruciat CM ,Hell K ,Folsch H ,Neupert W ,Stuart RA . Bcs1p, an AAA-family member, is a chaperone for the assembly of the cytochrome bc(1) complex. EMBO J 1999;18:5226-5233
CrossRef | Web of Science | Medline6
Nobrega FG ,Nobrega MP ,Tzagoloff A . BCS1, a novel gene required for the expression of functional Rieske iron-sulfur protein in Saccharomyces cerevisiae. EMBO J 1992;11:3821-3829
Web of Science | Medline7
Ogura T ,Wilkinson AJ . AAA+ superfamily ATPases: common structure -- diverse function. Genes Cells 2001;6:575-597
CrossRef | Web of Science | Medline8
Sauer RT ,Bolon DN ,Burton BM , et al. Sculpting the proteome with AAA(+) proteases and disassembly machines. Cell 2004;119:9-18
CrossRef | Web of Science | Medline9
Schagger H ,von Jagow G . Blue native electrophoresis for isolation of membrane protein complexes in enzymatically active form. Anal Biochem 1991;199:223-231
CrossRef | Web of Science | Medline10
Schagger H ,Pfeiffer K . The ratio of oxidative phosphorylation complexes I-V in bovine heart mitochondria and the composition of respiratory chain supercomplexes. J Biol Chem 2001;276:37861-37867
Web of Science | Medline11
Fellman V . The GRACILE syndrome, a neonatal lethal metabolic disorder with iron overload. Blood Cells Mol Dis 2002;29:444-450
CrossRef | Web of Science | Medline12
Visapaa I ,Fellman V ,Vesa J , et al. GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. Am J Hum Genet 2002;71:863-876
CrossRef | Web of Science | Medline13
dbSNP: a database of single nucleotide polymorphisms. National Human Genome Research Institute, The National Center for Biotechnology Information, 2005. (Accessed January 26, 2007, at http://www.ncbi.nlm.nih.gov/SNP/.)
14
Celera Discovery System. Celera Genomics, 2005. (Accessed January 26, 2007, at http://www.celera.com.)
15
Shi SR ,Key ME ,Kalra KL . Antigen retrieval in formalin-fixed, paraffin-embedded tissues: an enhancement method for immunohistochemical staining based on microwave oven heating of tissue sections. J Histochem Cytochem 1991;39:741-748
CrossRef | Web of Science | Medline16
Hill JE ,Myers AM ,Koerner TJ ,Tzagoloff A . Yeast/E. coli shuttle vectors with multiple unique restriction sites. Yeast 1986;2:163-167
CrossRef | Web of Science | Medline17
Yang J ,Liu X ,Bhalla K , et al. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 1997;275:1129-1132
CrossRef | Web of Science | Medline18
Bodemer C ,Rotig A ,Rustin P , et al. Hair and skin disorders as signs of mitochondrial disease. Pediatrics 1999;103:428-433
CrossRef | Web of Science | Medline19
Muller FL ,Liu Y ,Van Remmen H . Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem 2004;279:49064-49073
CrossRef | Web of Science | Medline20
Yamada K ,Kunishima N ,Mayanagi K , et al. Crystal structure of the Holliday junction migration motor protein RuvB from Thermus thermophilus HB8. Proc Natl Acad Sci U S A 2001;98:1442-1447
CrossRef | Web of Science | Medline21
Puchowicz MA ,Varnes ME ,Cohen BH ,Friedman NR ,Kerr DS ,Hoppel CL . Oxidative phosphorylation analysis: assessing the integrated functional activity of human skeletal muscle mitochondria -- case studies. Mitochondrion 2004;4:377-385
CrossRef | Web of Science | Medline22
Lesnefsky EJ ,Chen Q ,Moghaddas S ,Hassan MO ,Tandler B ,Hoppel CL . Blockade of electron transport during ischemia protects cardiac mitochondria. J Biol Chem 2004;279:47961-47967
CrossRef | Web of Science | Medline23
Wenchich L ,Drahota Z ,Honzik T , et al. Polarographic evaluation of mitochondrial enzymes activity in isolated mitochondria and in permeabilized human muscle cells with inherited mitochondrial defects. Physiol Res 2003;52:781-788
Web of Science | Medline24
Folsch H ,Guiard B ,Neupert W ,Stuart RA . Internal targeting signal of the BCS1 protein: a novel mechanism of import into mitochondria. EMBO J 1996;15:479-487
Web of Science | Medline25
Stan T ,Brix J ,Schneider-Mergener J ,Pfanner N ,Neupert W ,Rapaport D . Mitochondrial protein import: recognition of internal import signals of BCS1 by the TOM complex. Mol Cell Biol 2003;23:2239-2250
CrossRef | Web of Science | Medline26
Frickey T ,Lupas AN . Phylogenetic analysis of AAA proteins. J Struct Biol 2004;146:2-10
CrossRef | Web of Science | Medline27
Walker B ,Bayley H . A pore-forming protein with a protease-activated trigger. Protein Eng 1994;7:91-97
CrossRef | Medline28
Hanson PI ,Whiteheart SW . AAA+ proteins: have engine, will work. Nat Rev Mol Cell Biol 2005;6:519-529
CrossRef | Web of Science | Medline29
Petruzzella V ,Tiranti V ,Fernandez P ,Ianna P ,Carrozzo R ,Zeviani M . Identification and characterization of human cDNAs specific to BCS1, PET112, SCO1, COX15, and COX11, five genes involved in the formation and function of the mitochondrial respiratory chain. Genomics 1998;54:494-504
CrossRef | Web of Science | Medline30
de Lonlay P ,Valnot I ,Barrientos A , et al. A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure. Nat Genet 2001;29:57-60
CrossRef | Web of Science | Medline31
Kregel KC, Zhang HJ. An integrated view of oxidative stress in aging: basic mechanisms, functional effects and pathological considerations. Am J Physiol Regul Integr Comp Physiol (in press).
32
Turrens JF . Mitochondrial formation of reactive oxygen species. J Physiol 2003;552:335-344
CrossRef | Web of Science | Medline33
Armstrong JS ,Yang H ,Duan W ,Whiteman M . Cytochrome bc(1) regulates the mitochondrial permeability transition by two distinct pathways. J Biol Chem 2004;279:50420-50428
CrossRef | Web of Science | Medline34
Lefebvre PP ,Malgrange B ,Lallemend F ,Staecker H ,Moonen G ,Van De Water TR . Mechanisms of cell death in the injured auditory system: otoprotective strategies. Audiol Neurootol 2002;7:165-170
CrossRef | Web of Science | Medline
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Francisca Diaz, Heike Kotarsky, Vineta Fellman, Carlos T. Moraes. (2011) Mitochondrial disorders caused by mutations in respiratory chain assembly factors. Seminars in Fetal and Neonatal Medicine 16:4, 197-204
CrossRef6
Joél Smet, Boel Paepe, Sara Seneca, Willy Lissens, Heike Kotarsky, Linda Meirleir, Vineta Fellman, Rudy Coster. (2011) Complex III staining in blue native polyacrylamide gels. Journal of Inherited Metabolic Disease 34:3, 741-747
CrossRef7
Salvatore DiMauro. (2011) A history of mitochondrial diseases. Journal of Inherited Metabolic Disease 34:2, 261-276
CrossRef8
Cameron K. Tebbi, Thora S. Steffensen, Thordur Thorkelsson, Jens A. Gudmundsson, Enid Gilbert-Barness. (2011) Clinicopathologic Conference: Multiple Fetal Demises, Lactic Acidosis and Hepatic Iron Accumulation. Fetal & Pediatric Pathology 30:2, 77-87
CrossRef9
Per Levéen, Heike Kotarsky, Matthias Mörgelin, Riitta Karikoski, Eskil Elmér, Vineta Fellman. (2011) The GRACILE mutation introduced into Bcs1l causes postnatal complex III deficiency: A viable mouse model for mitochondrial hepatopathy. Hepatology 53:2, 437-447
CrossRef10
Paradi Mirmirani, Kathie P. Huang, Vera H. Price. (2011) A practical, algorithmic approach to diagnosing hair shaft disorders. International Journal of Dermatology 50:1, 1-12
CrossRef11
A.S. Knisely, Romil Saxena. 2011. Intrahepatic Cholestasis. , 139-157.
CrossRef12
Marni J. Falk. (2010) Neurodevelopmental Manifestations of Mitochondrial Disease. Journal of Developmental & Behavioral Pediatrics 31:7, 610-621
CrossRef13
Helen A.L. Tuppen, Janev Fehmi, Birgit Czermin, Paola Goffrini, Francesca Meloni, Iliana Ferrero, Langping He, Emma L. Blakely, Robert McFarland, Rita Horvath, Douglass M. Turnbull, Robert W. Taylor. (2010) Long-term survival of neonatal mitochondrial complex III deficiency associated with a novel BCS1L gene mutation. Molecular Genetics and Metabolism 100:4, 345-348
CrossRef14
María Morán, Lorena Marín-Buera, M. Carmen Gil-Borlado, Henry Rivera, Alberto Blázquez, Sara Seneca, María Vázquez-López, Joaquín Arenas, Miguel A. Martín, Cristina Ugalde. (2010) Cellular pathophysiological consequences of BCS1L mutations in mitochondrial complex III enzyme deficiency. Human Mutation 31:8, 930-941
CrossRef15
Shane L. Rea, Brett H. Graham, Eiko Nakamaru-Ogiso, Adwitiya Kar, Marni J. Falk. (2010) Bacteria, yeast, worms, and flies: Exploiting simple model organisms to investigate human mitochondrial diseases. Developmental Disabilities Research Reviews 16:2, 200-218
CrossRef16
Salvatore DiMauro, Caterina Garone. (2010) Historical perspective on mitochondrial medicine. Developmental Disabilities Research Reviews 16:2, 106-113
CrossRef17
Agnès Rötig. (2010) Genetic bases of mitochondrial respiratory chain disorders. Diabetes & Metabolism 36:2, 97-107
CrossRef18
A. G. Messenger, D. A. R. de Berker, R. D. Sinclair. 2010. Disorders of Hair. , 1-100.
CrossRef19
Kaye N. Truscott, Bradley R. Lowth, Philip R. Strack, David A. Dougan. (2010) Diverse functions of mitochondrial AAA+ proteins: protein activation, disaggregation, and degradationThis paper is one of a selection of papers published in this special issue entitled 8th International Conference on AAA Proteins and has undergone the Journal's usual peer review process.. Biochemistry and Cell Biology 88:1, 97-108
CrossRef20
(2009) Clinical and biochemical spectrum of mitochondrial complex III deficiency caused by mutations in the BCS1L gene. Clinical Genetics 75:6, 585-587
CrossRef21
Stefano Di Donato. (2009) Multisystem manifestations of mitochondrial disorders. Journal of Neurology 256:5, 693-710
CrossRef22
Alberto Blázquez, Mari Carmen Gil-Borlado, María Morán, Alfonso Verdú, María Rosario Cazorla-Calleja, Miguel A. Martín, Joaquín Arenas, Cristina Ugalde. (2009) Infantile mitochondrial encephalomyopathy with unusual phenotype caused by a novel BCS1L mutation in an isolated complex III-deficient patient. Neuromuscular Disorders 19:2, 143-146
CrossRef23
François-Guillaume Debray, Marie Lambert, Grant A Mitchell. (2008) Disorders of mitochondrial function. Current Opinion in Pediatrics 20:4, 471-482
CrossRef24
Denise M Kirby, David R Thorburn. (2008) Approaches to Finding the Molecular Basis of Mitochondrial Oxidative Phosphorylation Disorders. Twin Research and Human Genetics 11:4, 395-411
CrossRef25
Amy S. Cheng, Susan J. Bayliss. (2008) The genetics of hair shaft disorders. Journal of the American Academy of Dermatology 59:1, 1-22
CrossRef26
Vineta Fellman, Susanna Lemmelä, Antti Sajantila, Helena Pihko, Irma Järvelä. (2008) Screening of BCS1L mutations in severe neonatal disorders suspicious for mitochondrial cause. Journal of Human Genetics 53:6, 554-558
CrossRef27
Richard H. Haas, Sumit Parikh, Marni J. Falk, Russell P. Saneto, Nicole I. Wolf, Niklas Darin, Lee-Jun Wong, Bruce H. Cohen, Robert K. Naviaux. (2008) The in-depth evaluation of suspected mitochondrial disease. Molecular Genetics and Metabolism 94:1, 16-37
CrossRef28
O. Dereure. (2008) Mutations faux sens du gène BCS1L dans le syndrome de Bjornstad. Annales de Dermatologie et de Vénéréologie 135:1, 86
CrossRef29
B.H. Thiers. (2008) Missense Mutations in the BCS1L Gene as a Cause of the Björnstad Syndrome. Yearbook of Dermatology and Dermatologic Surgery 2008, 245-246
CrossRef30
Susan Roehl White, Brett Lauring. (2007) AAA+ ATPases: Achieving Diversity of Function with Conserved Machinery. Traffic 8:12, 1657-1667
CrossRef
