Alternative titles; symbols
HGNC Approved Gene Symbol: MT-CYB
SNOMEDCT: 267044007, 447292006, 58610003; ICD10CM: H47.22;
Cytochrome b (MTCYB) is the only mitochondrial DNA (mtDNA) encoded subunit of respiratory Complex III (ubiquinol:ferrocytochrome c oxidoreductase, or cytochrome bc1, complex, EC 1.10.2.2). Complex III is located within the mitochondrial inner membrane and is the second enzyme in the electron transport chain of mitochondrial oxidative phosphorylation. It catalyzes the transfer of electrons from ubiquinol (reduced Coenzyme Q10) to cytochrome c and utilizes the energy to translocate protons from inside the mitochondrial inner membrane to outside. Bovine Complex III has been resolved into 11 polypeptides by SDS-polyacrylamide gels (PAGE), designated I-XI (Schagger et al., 1986; Gonzalez-Halphen et al., 1988). These subunits include core proteins I and II, cytochrome b (subunit III), cytochrome c1 (subunit IV), the Rieske iron-sulfur protein (subunit V), and several smaller polypeptides. Subunits III, IV, and V are the major redox proteins in the complex and are present in the molar ratio 2:1:1 (Rieske, 1976). The core proteins I and II are essential for the assembly and proper association of the redox centers in Complex III, though they do not contain redox centers (Linke and Weiss, 1986; Crivellone et al., 1988; Oudshoorn et al., 1987; Tzagoloff et al., 1986).
MTCYB is a highly evolutionarily conserved, hydrophobic protein containing 8 or 9 transmembrane domains and 2 heme groups. The 2 hemes differ in redox potential and difference spectra and have been designated b-562--the high potential heme, and b-566--the low potential heme (Esposti et al., 1993; Wikstrom et al., 1981; Saraste, 1984). Cytochrome b together with core proteins I and II comprise the central components of Complex III. The Rieske iron-sulfur protein is on the cytoplasmic side of the inner membrane and accepts electrons from MTCYB (Gonzalez-Halphen et al., 1988). The electrons are then transferred to cytochrome c1 which contains 1 membrane-spanning domain, a covalently bound heme, and is also located on the outside of the mitochondrial inner membrane. Cytochrome c1 transfers electrons to cytochrome c (Weiss et al., 1987).
The mechanism by which proton translocation is linked to electron transport has been studied intensively for Complex III. Two important models are the proton-motive ubiquinone (Q) cycle and the b-cycle (Mitchell, 1976; Hatefi, 1985). Both models link proton translocation and electron transfer through ubiquinone redox intermediates (Hatefi, 1985; Wikstrom and Krab, 1986).
MTCYB is encoded by the guanine-rich heavy (H) strand of the mtDNA and located between nucleotide pairs (nps) 14747 and 15887 (Anderson et al., 1981; Wallace et al., 1994). It is maternally inherited along with the mtDNA (Giles et al., 1980; Case and Wallace, 1981).
The MTCYB gene encompasses 1140 nps of mtDNA and encodes a single polypeptide without introns. The mRNA has a 4-np, 5-prime noncoding region followed by the AUG start codon, and ends with the U of the UAA termination codon (Anderson et al., 1981; Ojala et al., 1981; Montoya et al., 1981; Wallace et al., 1994). It is transcribed as a part of the polycistronic H-strand transcript, flanked by the tRNAGlu and tRNAThr transcripts. These tRNAs are cleaved out at the transcript freeing transcript 11, the MTCYB mRNA. The mRNA is then polyadenylated completing the termination codon (Anderson et al., 1981; Ojala et al., 1981: Attardi et al., 1982).
The predicted molecular weight (MW) of MTCYB is 42.7 kD (Anderson et al., 1981; Wallace et al., 1994). However, its high hydrophobicity results in variable migration on SDS-PAGE with an altered apparent molecular weight. Using Tris-glycine buffer it migrates at approximately 27.5 kD (Oliver et al., 1984; Oliver and Wallace, 1982; Wallace et al., 1986), whereas in urea-phosphate buffer it migrates at about 29 kD (Chomyn et al., 1985).
Restriction site polymorphisms have been identified at the following nucleotide position for the indicated enzymes (where '+' = site gain, '-' = site loss relative to the reference sequence, Anderson et al., 1981): Alu I: +14899, +15245, +15437, +15606, -15776; Ava II: +15487, +15591, +15882; Dde I: +14773, +14923, -15073, -15238, -15250, +15434, +15660, +15727, +15751/15754; Hae II: -14858, -15002; Hae III: +14749, +14899, -15047, -15073, -15172, +15431, +15520, +15595, -15883; Hha I: -14859, -15003; HincII: +14648/15765; HinfI: +15005, -15234, -15375, -15723; Mbo I: +14749, -14869, -15060, +15195/15221, +15235, +15397, -15591, +15790/16373; Msp I: +15485; Rsa I: +15346, +15412, -15812, +15872; Taq I: -14956, +15549, +15861; Xho I: -15068 (Wallace et al., 1994).
MTCYB has phenotypically relevant alleles that contribute to Leber hereditary optic neuropathy (LHON; 535000), including MTCYB*LHON15257A (516020.0001) and MTCYB*LHON15812A (516020.0002).
Spiro et al. (1970) described a 46-year-old man and his 16-year-old son with progressive ataxia, predominantly proximal muscle weakness, areflexia, extensor plantar responses, dementia, and concomitant nonspecific myopathic and neuropathic changes in muscle. Studies of muscle mitochondria showed very loose coupling of oxidative phosphorylation and marked reduction in cytochrome b content, representing a defect in complex III. Morgan-Hughes et al. (1982) reported a patient with a defect at the cytochrome b level in the mitochondrial respiratory chain. The patient had onset of myoclonus followed by generalized weakness, ataxia, and mental confusion. Patients with complex III deficiency reported by Darley-Usmar et al. (1983) and Hayes et al. (1984) had combinations of muscular weakness, ataxia, exercise intolerance, and ocular myopathy. Most problems were initially noted in childhood and worsened with age.
Andreu et al. (1999) described 5 new patients with exercise intolerance in whom they identified mutations in the MTCYB gene, and reviewed the characteristics of 4 patients previously identified. They concluded that there is a sporadic form of mitochondrial myopathy in which exercise intolerance is the predominant symptom. Each of the mutations in the MTCYB gene impaired the enzymatic function of the cytochrome b protein. In these patients, the clinical manifestations included progressive exercise intolerance, proximal limb weakness, and in some cases attacks of myoglobinuria. There was no maternal inheritance and there were no mutations in tissues other than muscle. The absence of these findings suggested that the disorder is due to somatic mutations in myogenic stem cells after germ-layer differentiation. All of the point mutations involved the substitution of adenine for guanine, but all were in different locations.
Keightley et al. (2000) stated that the report by Dumoulin et al. (1996) was the first instance of isolated complex III deficiency in which mutation in the cytochrome b gene was shown to be pathogenic, after which 12 additional pathogenic mutations in this gene were described in various studies. Most of the patients presented with the predominant feature of severe exercise intolerance, sometimes including muscle weakness and/or myoglobinuria. Keightley et al. (2000) reinvestigated a young woman, originally reported by Kennaway et al. (1984), who presented with exercise intolerance and lactic acidosis associated with severe deficiency of complex III and who responded to therapy with menadione and ascorbate. She gradually developed symptoms of a mitochondrial encephalomyopathy. Immunocytochemistry of serial sections of muscle showed a mosaic of fibers that reacted poorly with antibodies to subunits of complex III but reacted normally with antibodies to subunits of complex I, II, or IV, suggesting a mutation of mtDNA. This experience demonstrated the diagnostic value of immunocytochemistry in identifying specific respiratory-chain deficiencies and, potentially, distinguishing between nuclear- and mtDNA-encoded defects. Keightley et al. (2000) demonstrated a stop codon mutation, 15242G-A (516020.0007), in the mtDNA-encoded cytochrome b gene, resulting in loss of the last 215 amino acids of cytochrome b. The mutation was heteroplasmic and was present in 87% of skeletal muscle and in a low percentage (0.7%) of blood. The mutation was also present in several other tissues, including hair roots, indicating that it must have arisen either very early in embryogenesis, before separation of the primary germ layers, or in the maternal germline.
In cells from a patient with parkinsonism and mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS; 540000) who harbored a 4-bp deletion in the MTCYB gene, Rana et al. (2000) found defective synthesis of the protein, defective oxidative phosphorylation, defective complex III synthesis and activity, and increased hydrogen peroxide production. In the patient, CSF lactate was 10-fold higher than in serum, which may indicate accumulation of the mutation in the CNS. Rana et al. (2000) suggested that the 4-bp deletion may increase reactive oxygen species and contribute to a variable phenotype via a mechanism different from reduced energy production.
Legros et al. (2001) analyzed the MTCYB gene in 21 patients with a mitochondrial disease (a group of 7 patients had an isolated complex III defect and a group of 14 patients had a mitochondrial disorder without an isolated complex III defect) and 146 healthy adult control subjects. Gene sequencing was used in the patients, whereas DGGE was performed in the control group. Altogether, 38 variations in the MTCYB gene sequence were identified in the patients and in the control population. The functional relevance of the sequence variations were evaluated using indirect criteria (such as the nature of the mutation, its frequency in controls, and the phylogenetic conservation of the mutated amino acid) and enzymologic and Western blot analysis of complex III. Two original deleterious mutations were found in the group of 7 patients with overt complex III defect. Both mutations (15150G-A; 516020.0008 and 15197T-C; 516020.0009) were heteroplasmic and restricted to muscle tissue and both patients had an isolated intolerance to exercise from their late childhood. Spectrophotometric analysis of the respiratory chain showed that the complex III activity was extremely decreased in muscle but normal in leukocytes and skin fibroblasts. The findings underlined the pathogenic relevance of the 2 heteroplasmic mutations and further confirmed that cytochrome b alterations cause isolated complex III defect in humans.
Andreu et al. (1998, 1999) noted that mutations in the MTCYB gene are often sporadic and can arise during embryogenesis, affecting a limited number of cells and resulting in tissue-specific phenotypes. Andreu et al. (2000) identified a point mutation in the MTCYB gene (516020.0011) that was associated with histiocytoid cardiomyopathy (500000).
Fliss et al. (2000) identified a somatic 21-bp deletion in the MTCYB gene in tumor tissue from a patient with bladder cancer (109800). Dasgupta et al. (2008) found that overexpression of the 21-bp deletion identified by Fliss et al. (2000) in murine bladder cancer cells resulted in increased tumor growth and an invasive phenotype in vitro and after injection into mice. Increased tumor growth was associated with shifts toward glycolysis and production of reactive oxygen species (ROS). Rapid cell cycle progression was associated with upregulation of the NFKB (164011) signaling pathway, and inhibition of ROS or NFKB diminished tumor growth in vitro. Transfection of the 21-bp deletion into human uroepithelial cells resulted in similar effects. The findings suggested that mitochondrial mutations may contribute to tumor growth.
This allele changes the highly conserved aspartate at amino acid 171 to an asparagine (D171N). This mutation is located in a region of approximately 20 conserved amino acids that are adjacent to an invariant histidine residue (His-183) that is involved in ligating the low potential b-566 heme (Brown et al., 1992). This allele displays characteristics of both primary and secondary LHON mutations and hence may significantly contribute to the disease process. In most, but not all cases, the MTCYB*LHON15257A allele has been associated with the primary LHON mutation MTND6*LHON14484A and the secondary mutation MTND5*LHON13708A. Individuals harboring this mtDNA haplotype may also harbor the allele MTCYB*LHON15812A, and the MTCYB*LHON15257A allele has been found in association with the MTND2*LHON5244A mutation in 1 case. Overall, individuals carrying the MTCYB*LHON15257A variant make up approximately 9% of LHON patients, but the mutation is also seen in 0.3% of population controls. Families with this variant together with MTND6*LHON14484A have between 27 and 80% of maternal relatives affected, of which between 75 and 100% are males. Approximately 28% of affected individuals experience visual recovery (Brown et al., 1991; Brown et al., 1992; Heher and Johns, 1993; Huoponen et al., 1993; Johns and Neufeld, 1991; Johns et al., 1993).
Mackey et al. (1996) surveyed 159 families of northern European extraction with at least 1 case of LHON. In 97% of these families, 1 of the 3 previously identified, so-called primary mutations (3460, 11778, and 14484) were found. In no instance was the 15257 mutation found, prompting Mackey et al. (1996) to suggest that it is not a primary mutation causing LHON. They admitted that it might represent a primary causative mutation with penetrance sufficiently high to produce a clear-cut, multigenerational pattern of maternal inheritance. They excluded single cases of LHON from their study.
This allele converts the moderately conserved aliphatic amino acid (either alanine, valine, or isoleucine) at 356 to a methionine (V356M). This is a secondary LHON mutation which is regularly found associated with the additional LHON mutations: MTND5*LHON13708A, MTND6*LHON14484A, and MTCYB*LHON15257A. While the mutation does not cause LHON, it may increase the probability of phenotypic expression (Brown et al., 1991; Brown et al., 1992; Johns and Neufeld, 1991).
Early on, Warburg (1956) suggested that alterations of oxidative phosphorylation in tumor cells play a causative role in cancerous growth. Interest in mitochondria with regard to neoplasia has revived, largely because of their role in apoptosis and other aspects of tumor biology. The mitochondrial genome is particularly susceptible to mutations because of the high level of reactive oxygen species (ROS) generated in this organelle, coupled with a low level of DNA repair. In a colorectal cancer, Polyak et al. (1998) found 3 somatic mutations in the mitochondrial genome. Two occurred in the MTCYB gene: a 14985G-A change leading to an arg80-to-his substitution; and a 15572T-C transition, leading to a phe276-to-leu substitution (516020.0004). The third mutation occurred in the MTCO1 gene; see 516040.0002.
See 516020.0003 and Polyak et al. (1998).
Bouzidi et al. (1993) found low activity of respiratory chain complex III in muscle from a 25-year-old man with exercise intolerance in whom Dumoulin et al. (1996) later identified a missense mutation, 15615G-A, in the mitochondrial cytochrome b gene, the only mtDNA encoded subunit of complex III. The findings in this patient were reviewed by Andreu et al. (1999) as part of a series of 9 cases, 5 of their own and 4 reported by others.
One of the 5 patients with exercise intolerance due to mutation in the cytochrome b gene of mitochondrial DNA identified by Andreu et al. (1999) was a 52-year-old woman who had had exercise intolerance since childhood with muscle weakness and myopathy on electromyography and hyperlactic acidemia. The patient showed 'ragged-red fibers' (22%) on muscle biopsy. The nucleotide substitution resulted in a gly34-to-ser amino acid substitution. Lactic acidosis in the resting state was found in 4 of the 5 patients studied by Andreu et al. (1999).
Keightley et al. (2000) presented observations on a 34-year-old woman followed for 17 years. She had a history of progressive exercise intolerance and lactic acidosis starting at approximately 9 years of age. By age 19 years she had clear evidence of encephalopathy, with emotional lability, seizures, abnormal EEG, intermittent visual hallucinations, and depression. The authors identified a stop mutation, 15242G-A, predicting a gly166-to-ter truncation of the protein with loss of 215 amino acids, representing 57% of the C terminus of cytochrome b.
In a patient with isolated intolerance to exercise from late childhood, Legros et al. (2001) identified a nonsense mutation, 15150G-A, predicting a trp135-to-ter truncation of the protein. The family history was negative. The mutation was restricted to muscle tissue where it represented 60% of the mtDNA molecules. The mutation was absent in a control population of 146 healthy adults. Spectrophotometric analysis showed that the complex III activity was extremely decreased in muscle but normal in leukocytes and skin fibroblasts. Western blot analysis of complex III in muscle showed undetectable cytochrome b protein.
In a patient with isolated intolerance to exercise from late childhood, Legros et al. (2001) identified a missense mutation, 15197T-C, resulting in a ser151-to-pro amino acid substitution. The serine at position 151 was highly conserved and the mutation constituted an important modification in the physicochemical properties of the amino acid. The family history was negative. The mutation was restricted to muscle tissue where it represented 80% of the mtDNA molecules. The mutation was absent in a control population of 146 healthy adults. Spectrophotometric analysis showed that the complex III activity was extremely decreased in muscle but normal in leukocytes and skin fibroblasts. Western blot analysis of complex III in muscle showed a reduced amount of cytochrome b protein.
Whereas most mutations in the MTCYB gene had been reported to cause a homogeneous phenotype of pure exercise intolerance, Wibrand et al. (2001) described a 15579A-G mutation associated with a selective decrease of muscle complex III activity in a patient who, besides severe exercise intolerance, also had multisystem manifestations (deafness, mental retardation, retinitis pigmentosa, cataract, growth retardation, epilepsy). The 15579A-G mutation was heteroplasmic in muscle (88%) and leukocytes (15%), and changed a highly conserved tyrosine to cysteine at amino acid position 278.
In an infant girl who died of cardiac arrest at the age of 4 weeks and was found to have typical pathologic features of histiocytoid cardiomyopathy (500000), Andreu et al. (2000) identified a point mutation in the MTCYB gene, a G-to-A transition at nucleotide 15498, resulting in a gly251-to-asp substitution. The mutation, which was heteroplasmic and fulfilled all accepted criteria for pathogenicity, was thought to impair the function of the holoenzyme as deduced from its effects on the crystal structure of ubiquinol cytochrome c oxidoreductase. The infant showed involvement of other organs, including liver (hepatic steatosis) and kidney (acute tubular necrosis).
Schuelke et al. (2002) reported a patient with neurologic symptoms starting in infancy and manifesting as hypotonia, retarded language and motor development, dysdiadochokinesia, gait ataxia, small head circumference, cerebellar hypoplasia, and exercise intolerance. In addition, he had hypertrophic cardiomyopathy, retinitis pigmentosa, and features of septooptic dysplasia; the latter 2 symptoms had not previously been described in association with complex III deficiency. The patient was found to have a 14849T-C mutation in the MTCYB gene, resulting in a substitution of a highly conserved serine for proline at position 35. The mutation was heteroplasmic in muscle (69%) and fibroblasts (12%), although residual complex III activity was the same in both tissues (70%). The authors suggested that the mutation may lead to increased reactive oxygen species, which may play a role in the pathogenic findings.
In a patient with diminished activity of complex III of the mitochondrial respiratory chain, De Coo et al. (1999) identified a heteroplasmic 4-bp deletion in a highly conserved portion of the cytochrome b gene. The deletion was predicted to lead to a truncated protein. The patient had a severe progressive disorder beginning at age 6 years with difficulty in fine motor coordination and concentration. He later developed behavioral changes, parkinsonism, myoclonus, extensor plantar responses, and cerebral infarcts. More than 95% of the mtDNA in muscle was mutated.
Okura et al. (2003) examined the possible relationship between the Mt15497G-A polymorphism and obesity (601665) by studying middle-aged and elderly Japanese individuals (825 women and 906 men). After adjusting for age and smoking, they found that body weight, body mass index, waist and hip circumferences, fat mass, fat-free mass, intraabdominal fat, and triglycerides were significantly greater in women with the A allele compared with the G allele. For men, waist-to-hip ratio was significantly greater, and waist circumference, intraabdominal fat, and triglycerides had a trend to be significantly greater, in subjects with the A allele compared with the G allele. These data suggested that the Mt15497 polymorphism may be associated with obesity-related variables and lipid metabolism.
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