HGNC Approved Gene Symbol: MB
Cytogenetic location: 22q12.3 Genomic coordinates (GRCh38): 22:35,606,764-35,623,354 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q12.3 | Myopathy, sarcoplasmic body | 620286 | Autosomal dominant | 3 |
The MB gene encodes myoglobin, a cytoplasmic globular hemoprotein highly expressed in skeletal myofibers and cardiac myocytes. Myoglobin binds oxygen (O2) and facilitates its intracellular transport; it plays a role in the control of nitric oxide and reactive oxygen species (ROS) (summary by Olive et al., 2019).
Weller et al. (1984) and Akaboshi (1985) independently cloned human MB, which encodes a protein of 152 residues.
Weller et al. (1984) determined that the MB gene contains 3 exons spanning 10.4 kb.
Jeffreys et al. (1984) used DNA probes isolated from the cloned myoglobin gene to map the gene in human-rodent somatic cell hybrids. The myoglobin locus mapped to chromosome 22q11-q13. Julier et al. (1985) confirmed assignment to chromosome 22. Julier et al. (1985) concluded from multilocus linkage tests that the oncogene SIS locus is most likely distal to MB and that both are distal to IGL. The following tentative map was derived: cen--IGL--0.10--D22S1--0.20--MB--0.07--(SIS, P1).
Two structural variants of myoglobin were described by Boyer et al. (1963). Boulton et al. (1969) studied postmortem muscle from 2,500 persons. Two myoglobin variants were found, and in one of these substitution of lysine for glutamic acid at residue 53 was demonstrated. Later Boulton et al. (1970) described a variant myoglobin with substitution of glutamine for arginine at residue 139. A third substitution is tryptophan for arginine at residue 139 and a fourth is asparagine for lysine at residue 133 (Romero-Herrera and Lehmann (1971, 1974)).
Sarcoplasmic Body Myopathy
In affected members of 6 unrelated families of European descent with sarcoplasmic body myopathy (MYOSB; 620286), Olive et al. (2019) identified a heterozygous missense mutation in the MB gene (H98Y; 160000.0001). The mutation in the families was found through different methods, including whole-exome sequencing (F1 and F2), linkage analysis and candidate gene sequencing (F3), and direct sequencing of the MB gene (F4, F5, and F6). The mutation was confirmed by Sanger sequencing and segregated with the disorder in all families. It was not present in public databases, including gnomAD. Family F3 had previously been reported by Edstrom et al. (1980). Haplotype analysis did not reveal a founder effect, suggesting that H98Y is a recurrent mutation. Biochemical characterization indicated that the mutant myoglobin has altered O2 binding, exhibits a faster heme dissociation rate, and has a lower reduction potential compared to wildtype. Patient muscle biopsy samples showed evidence of lipid oxidation, increased intracellular superoxide, and increased sulfur content within sarcoplasmic bodies.
In a 75-year-old Asian woman with MYOSB, Hama et al. (2022) identified heterozygosity for the H98Y mutation in the MB gene. The mutation was found by whole-exome sequencing. Functional studies were not performed.
For a DNA sequence that contains tandem repeats but represents only a single locus, White (see Nakamura et al., 1987) introduced the designation variable number of tandem repeats (VNTR) locus. The first polymorphic locus discovered with an arbitrary DNA probe represented such a locus (Wyman and White, 1980; see 107750) with fragments of more than 15 different lengths observed in a small sample of unrelated persons. Subsequently, similar systems were observed in several other loci, such as the insulin gene (176730), the Harvey-ras gene (190020), the zeta-globin pseudogene (see 142310), the myoglobin gene, and the X-gene region of hepatitis B virus. This region of the HBV genome is thought to be the viral site of integration into the human genome and thus could be considered recombinogenic in a manner similar to the long terminal repeat regions of retroviruses. The repeats in these hypervariable loci have 11 to 60 basepairs. The length of each restriction fragment is a function of the number of copies of the tandem repeat sequence within the fragment. These hypervariable loci are highly informative markers for linkage studies. Jeffreys et al. (1985) found that a DNA probe based on a set of tandem repeats associated with the myoglobin locus can detect by hybridization to human genomic DNA a number of loci containing tandem repeats of similar sequence. The restriction fragment pattern revealed by the sum of the VNTR loci containing such related sequences, scattered through the genome, constitutes a 'fingerprint' unique to the individual.
Garry et al. (1998) created mice without myoglobin by targeted disruption of the myoglobin gene. The mice were fertile and exhibited normal exercise capacity and a normal ventilatory response to hypoxia. Although heart and soleus muscles were depigmented, they functioned normally in standard in vitro assays of muscle performance across a range of work conditions and oxygen availability. These data demonstrated that myoglobin is not essential to meet the metabolic requirements of pregnancy or exercise in a terrestrial mammal, and raise new questions about oxygen transport and metabolic regulation in working muscles. Whether simple diffusion is enough or other mechanisms exist to facilitate high rates of oxygen transport to working myocytes remained to be elucidated.
Godecke et al. (1999) used homologous recombination to delete exon 2 of the mouse Mb gene. They found that Mb -/- mice appeared phenotypically normal but had significantly elevated levels of hemoglobin and an increase in coronary flow and coronary reserve. Histologic analysis demonstrated increased capillary density in the hearts of Mb-deficient mice. Godecke et al. (1999) concluded that disruption of myoglobin results in the activation of multiple compensatory mechanisms that steepen the pO2 gradient to mitochondria, suggesting that myoglobin is important for the delivery of oxygen to mitochondria.
In affected members of 6 unrelated families of European descent with sarcoplasmic body myopathy (MYOSB; 620286), Olive et al. (2019) identified a heterozygous c.292C-T transition in the MB gene, resulting in a his98-to-tyr (H98Y) substitution at a highly conserved residue in the proximity of the oxygen-binding heme group. The mutation in the families was found through different methods, including whole-exome sequencing (F1 and F2), linkage analysis and candidate gene sequencing (F3), and direct sequencing of the MB gene (F4, F5, and F6). The mutation was confirmed by Sanger sequencing and segregated with the disorder in all families. It was not present in public databases, including gnomAD. Family F3 had previously been reported by Edstrom et al. (1980).
In a 75-year-old Asian woman with MYOSB, Hama et al. (2022) identified a heterozygous H98Y mutation in the MB gene. The mutation was found by whole-exome sequencing. Functional studies were not performed.
Hofbauer et al. (2022) demonstrated that the mutant H98Y protein showed increased reactivity toward hydrogen peroxide, had a tendency to form aggregates, and was more prone to heme bleaching compared to wildtype. These effects result in impaired oxygen binding capacity and faster heme dissociation compared to wildtype. The biochemical alterations likely play a role in the pathogenesis of the disease.
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Hama, Y., Mori-Yoshimura, M., Aizawa, K., Oya, Y., Nakamura, H., Inoue, M., Iida, A., Sato, N., Nonaka, I., Nishino, I., Takahashi, Y. Myoglobinopathy affecting facial and oropharyngeal muscles. Neuromusc. Disord. 32: 516-520, 2022. [PubMed: 35527200] [Full Text: https://doi.org/10.1016/j.nmd.2022.02.010]
Hofbauer, S., Pignataro, M., Borsari, M., Bortolotti, C. A., Di Rocco, G., Ravenscroft, G., Furtmuller, P. G., Obinger, C., Sola, M., Battistuzzi, G. Pseudoperoxidase activity, conformational stability, and aggregation propensity of the His98Tyr myoglobin variant: implications for the onset of myoglobinopathy. FEBS J. 289: 1105-1117, 2022. [PubMed: 34679218] [Full Text: https://doi.org/10.1111/febs.16235]
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Julier, C., Lathrop, M., Lalouel, J. M., Reghis, A., Szajnert, M. F., Kaplan, J. C. New restriction fragment length polymorphisms on human chromosome 22 at loci SIS, MB and IGLV. (Abstract) Cytogenet. Cell Genet. 40: 664 only, 1985.
Julier, C., Reghis, A., Szajnert, M. F., Kaplan, J. C., Lathrop, G. M., Lalouel, J. M. A preliminary linkage map of human chromosome 22. (Abstract) Cytogenet. Cell Genet. 40: 665 only, 1985.
Nakamura, Y., Leppert, M., O'Connell, P., Wolff, R., Holm, T., Culver, M., Martin, C., Fujimoto, E., Hoff, M., Kumlin, E., White, R. Variable number of tandem repeat (VNTR) markers for human gene mapping. Science 235: 1616-1622, 1987. [PubMed: 3029872] [Full Text: https://doi.org/10.1126/science.3029872]
Olive, M., Engvall, M., Ravenscroft, G., Cabrera-Serrano, M., Jiao, H., Bortolotti, C. A., Pignataro, M., Lambrughi, M., Jiang, H., Forrest, A. R. R., Benseny-Cases, N., Hofbauer, S., and 32 others. Myoglobinopathy is an adult-onset autosomal dominant myopathy with characteristic sarcoplasmic inclusions. Nature Commun. 10: 1396, 2019. [PubMed: 30918256] [Full Text: https://doi.org/10.1038/s41467-019-09111-2]
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