Alternative titles; symbols
HGNC Approved Gene Symbol: BOLA3
SNOMEDCT: 1208486005;
Cytogenetic location: 2p13.1 Genomic coordinates (GRCh38): 2:74,135,400-74,147,912 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
2p13.1 | Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia | 614299 | Autosomal recessive | 3 |
The BOLA3 gene encodes a protein that plays an essential role in the production of iron-sulfur (Fe-S) clusters for the normal maturation of lipoate-containing 2-oxoacid dehydrogenases and for the assembly of the mitochondrial respiratory chain complexes (summary by Cameron et al., 2011).
By searching databases for sequences similar to E. coli BolA, followed by RT-PCR of total brain RNA, Zhou et al. (2008) cloned human BOLA1 (613181), BOLA2 (613182), and BOLA3. The deduced 107-amino acid BOLA3 protein has an apparent N-terminal signal peptide, followed by a BolA domain containing a helix-turn-helix motif near its C terminus. RT-PCR analysis detected variable expression of 2 BOLA3 variants in all normal human tissues examined. BOLA3 was secreted into the culture medium of transfected COS-7 cells.
BOLA3 has 2 isoforms; isoform 2 lacks exon 3, which is present in isoform 1, resulting in different stop codons in the 2 transcripts. The longer isoform localizes to the mitochondria, whereas the shorter isoform localizes to the cytoplasm (Cameron et al., 2011).
Zhou et al. (2008) determined that the BOLA3 gene contains 4 coding exons.
Hartz (2009) mapped the BOLA3 gene to chromosome 2p13.1 based on an alignment of the BOLA3 sequence (GenBank BC017744) with the genomic sequence (GRCh37).
In a male infant, born of consanguineous East Indian parents, with fatal multiple mitochondrial dysfunctions syndrome-2 with hyperglycinemia (MMDS2; 614299), originally reported by Seyda et al. (2001), Cameron et al. (2011) identified a homozygous truncating mutation in the BOLA3 gene (613183.0001). Transduction of fibroblast lines with retroviral vectors expressing the mitochondrial, but not the cytosolic, isoform of BOLA3 corrected the defects in respiratory chain and oxoacid dehydrogenase complex function. The results indicated that BOLA3 plays an essential role in the production of iron-sulfur clusters for the normal maturation of lipoate-containing 2-oxoacid dehydrogenases and for the assembly of the respiratory chain complexes.
In 3 unrelated children with MMDS2, Baker et al. (2014) identified a homozygous nonsense mutation in the BOLA3 gene (R46X; 613183.0002). The mutation was found by sequencing of candidate genes involved in lipoate synthesis, as 2 of the patients who were studied had reduced lipoylated E2 subunits of the PDH and alpha-ketoglutarate dehydrogenase (alpha-KGDH) complexes. The unaffected parents were heterozygous for the mutation.
By whole-exome sequencing in 2 sibs (49720 and 56712) with MMDS2, Haack et al. (2013) identified a homozygous missense mutation (I67N) in the BOLA3 gene. The unaffected parents were heterozygous for the mutation.
By whole-exome sequencing in a female infant, born to nonconsanguineous parents, with MMDS2, Nikam et al. (2018) identified compound heterozygous mutations in the BOLA3 gene: the previously identified I67N mutation, inherited from her mother, and a novel variant, E74del (613183.0004), inherited from her father.
In a male infant, born of consanguineous East Indian parents, with fatal multiple mitochondrial dysfunctions syndrome-2 with hyperglycinemia (MMDS2; 614299), who was originally described by Seyda et al. (2001), Cameron et al. (2011) identified a homozygous 1-bp duplication (123dupA) in exon 2 of the BOLA3 gene, resulting in a frameshift and premature termination affecting both isoforms. Each unaffected parent was heterozygous for the mutation, which was not found in 68 control samples. Biochemical studies of patient fibroblasts showed a decrease in iron-sulfur cluster-containing respiratory chain complexes and a lack of detectable lipoate in the pyruvate dehydrogenase (PDH) and oxoacid dehydrogenase complexes. Only the longer mitochondrial isoform of BOLA3 rescued the respiratory chain and oxoacid dehydrogenase defects in immortalized fibroblasts.
In 3 unrelated children with multiple mitochondrial dysfunctions syndrome-2 with hyperglycinemia (MMDS2; 614299), Baker et al. (2014) identified a homozygous c.136C-T transition in exon 2 of the BOLA3 gene, resulting in an arg46-to-ter (R46X) substitution. The mutation was found by sequencing of candidate genes involved in lipoate synthesis, as 2 of the patients who were studied had reduced lipoylated E2 subunits of the pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (alpha-KGDH) complexes. The patients were of Caucasian, Indian, and African American descent, respectively; the unaffected parents were heterozygous for the mutation.
By whole-exome sequencing in 2 sibs (49720 and 56712) with multiple mitochondrial dysfunctions syndrome-2 with hyperglycinemia (MMDS2; 614299), Haack et al. (2013) identified a homozygous c.200T-A transversion (c.200T-A, NM_212552.2) in exon 3 of the BOLA3 gene, resulting in an ile67-to-asn (I67N) substitution at a conserved residue. The parents were heterozygous carriers of the mutation. Immunohistochemical investigations of assembled complex II in patient fibroblasts by confocal microscopy demonstrated clear reductions of succinate dehydrogenase and lipoic acid, which were restored after expression of wildtype BOLA3.
By whole-exome sequencing in a female infant with MMDS2, who was born to nonconsanguineous parents, Nikam et al. (2018) identified compound heterozygous mutations in the BOLA3 gene: I67N, inherited from her mother, and a 3-bp deletion (c.220_222del), resulting in a deletion of glutamine at residue 74 (E74del; 613183.0004), inherited from her father. Pyruvate dehydrogenase activity was decreased in the patient, similar to the decrease seen in a patient with known PDH deficiency. The authors noted that the E74 residue is less well conserved than the I67 residue and that this may have had a hypomorphic effect, leading to longer survival (15 months vs 3 months in the patients reported by Haack et al., 2013).
For discussion of the 3-bp deletion (c.222_221del) in the BOLA3 gene that was found in compound heterozygous state in 2 sibs with multiple mitochondrial dysfunctions syndrome-2 with hyperglycinemia (MMDS2; 614299) by Nikam et al. (2018), see 613183.0003.
Baker, P. R., Jr., Friederich, M. W., Swanson, M. A., Shaikh, T., Bhattacharya, K., Scharer, G. H., Aicher, J., Creadon-Swindell, G., Geiger, E., MacLean, K. N., Lee, W. T., Deshpande, C., and 17 others. Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. Brain 137: 366-379, 2014. [PubMed: 24334290] [Full Text: https://doi.org/10.1093/brain/awt328]
Cameron, J. M., Janer, A., Levandovskiy, V., MacKay, N., Rouault, T. A., Tong, W.-H., Ogilvie, I., Shoubridge, E. A., Robinson, B. H. Mutations in iron-sulfur cluster scaffold genes NFU1 and BOLA3 cause a fatal deficiency of multiple respiratory chain and 2-oxoacid dehydrogenase enzymes. Am. J. Hum. Genet. 89: 486-495, 2011. [PubMed: 21944046] [Full Text: https://doi.org/10.1016/j.ajhg.2011.08.011]
Haack, T. B., Rolinski, B., Haberberger, B., Zimmermann, F., Schum, J., Strecker, V., Graf, E., Athing, U., Hoppen, T., Wittig, I., Sperl, W., Freisinger, P., Mayr, J. A., Strom, T. M., Meitinger, T., Prokisch, H. Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings. J. Inherit. Metab. Dis. 36: 55-62, 2013. [PubMed: 22562699] [Full Text: https://doi.org/10.1007/s10545-012-9489-7]
Hartz, P. A. Personal Communication. Baltimore, Md. 12/17/2009.
Nikam, R. M., Gripp, K. W., Choudhary, A. K., Kandula, V. Imaging phenotype of multiple mitochondrial dysfunction syndrome 2, a rare BOLA3-associated leukodystrophy. Am. J. Med. Genet. 176A: 2787-2790, 2018. [PubMed: 30302924] [Full Text: https://doi.org/10.1002/ajmg.a.40490]
Seyda, A., Newbold, R. F., Hudson, T. J., Verner, A., MacKay, N., Winter, S., Feigenbaum, A., Malaney, S., Gonzalez-Halphen, D., Cuthbert, A. P., Robinson, B. H. A novel syndrome affecting multiple mitochondrial functions, located by microcell-mediated transfer to chromosome 2p14-2p13. Am. J. Hum. Genet. 68: 386-396, 2001. [PubMed: 11156534] [Full Text: https://doi.org/10.1086/318196]
Zhou, Y.-B., Cao, J.-B., Wan, B.-B., Wang, X.-R., Ding, G.-H., Zhu, H., Yang, H.-M., Wang, K.-S., Zhang, X., Han, Z.-G. hBolA, novel non-classical secreted proteins, belonging to different BolA family with functional divergence. Molec. Cell Biochem. 317: 61-68, 2008. [PubMed: 18548201] [Full Text: https://doi.org/10.1007/s11010-008-9809-2]