HGNC Approved Gene Symbol: CYB561
Cytogenetic location: 17q23.3 Genomic coordinates (GRCh38): 17:63,432,304-63,446,639 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q23.3 | Orthostatic hypotension 2 | 618182 | Autosomal recessive | 3 |
Cytochrome b561 is a major transmembrane protein that is specific to catecholamine and neuropeptide secretory vesicles of the adrenal medulla, pituitary gland, and other neuroendocrine tissues. This 30-kD cytochrome is present in both the small synaptic vesicles and the large dense core vesicles (chromaffin granules) of the tissues. Its role is to supply reducing equivalents to 2 monooxygenases, dopamine beta-hydroxylase (223360) in chromaffin granules and peptidylglycine alpha-amidating monooxygenase (170270) in neurosecretory vesicles. The cytochrome fulfills this role by catalyzing the transfer of electrons from a cytoplasmic donor, ascorbate, across a phospholipid bilayer to the luminal acceptor, semidehydroascorbate, in the interior of the vesicles. The continuously regenerated ascorbate within these vesicles is the immediate donor for the monooxygenases within the neuroendocrine secretory vesicles. Thus, cytochrome b561 is a transmembrane electron channel (summary by McBride et al., 1994).
Van den Berg et al. (2018) found ubiquitous expression of the CYB561 gene in the human brain, with strong expression in the cortex and hippocampus.
By injecting Xenopus oocytes with capped mRNAs for mouse b561 and incubating the oocytes in iron-rich (FeIII) medium, Vargas et al. (2003) showed that cytochrome b561 has significant ferric reductase activity.
Srivastava (1995) showed that the human CYB561 gene contains 5 exons spanning approximately 11 kb. Northern blots showed highest expression in colon cancer lines, T-cell lymphomas and K-562 cells.
McBride et al. (1994) demonstrated that the CYB561 gene is located on chromosome 17 by Southern analysis of DNA samples isolated from human/rodent somatic cell hybrids. Examination of several hybrids containing specific translocations at spontaneous breaks allowed regional localization to 17q11-qter.
In 4 adult women from 2 unrelated families with orthostatic hypotension-2 (ORTHYP2; 618182), van den Berg et al. (2018) identified homozygous mutations in the CYB561 gene (G88R, 600019.0001 and W44X, 600019.0002). The mutations, which were found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family from which parental DNA was available. Neurotransmitter analysis in patients and Cyb561-null mice (see ANIMAL MODEL), as well as molecular modeling, indicated that the mutations resulted in impaired CYB561 function, likely leading to a shortage of ascorbate recycling inside intracellular catecholamine secretory vesicles. As ascorbate is a cofactor for dopamine beta-hydroxylase (DBH; 609312), disrupted ascorbate recycling was suggested to cause functional DBH deficiency, defective norepinephrine synthesis from dopamine, and abnormal neurotransmitter metabolism.
Van den Berg et al. (2018) found that Cyb561-null mice had significantly decreased amounts of norepinephrine and normetanephrine in the adrenal gland and brain. In contrast, dopamine levels were normal, although dopamine catabolites were increased in the adrenal gland. The findings showed that dopamine biosynthesis is normal, and that the defect is downstream of dopamine.
In 2 adult Dutch sisters with orthostatic hypotension-2 (ORTHYP2; 618182), van den Berg et al. (2018) identified a homozygous c.262G-A transition (c.262G-A, NM_001915.3) in exon 3 of the CYB561 gene, resulting in a gly88-to-arg (G88R) substitution at a highly conserved residue in the third transmembrane domain. The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in non-Finnish European alleles in the gnomAD database, but another variant resulting in the same amino acid change (c.262G-C, G88R) was found in heterozygous state in 2 of the 126,628 alleles. Functional studies of the variant were not performed, but molecular modeling suggesting that the mutation could alter transmembrane anchoring or possibly ligand binding, consistent with impaired function.
In 2 adult American sisters with orthostatic hypotension-2 (ORTHYP2; 618182), van den Berg et al. (2018) identified a homozygous c.131G-A transition (c.131G-A, NM_001915.3) in exon 2 of the CYB561 gene, resulting in a trp44-to-ter (W44X) substitution. The mutation was predicted to truncate the protein between the first 2 transmembrane domains. The mutation was in 1 of 110,060 non-Finnish European alleles in the gnomAD database. Functional studies of the variant were not performed, but the authors suggested it would result in a loss of function.
McBride, O. W., Yi, H. F., Srivastava, M. The human cytochrome b561 gene (CYB561) is located at 17q11-qter. Genomics 21: 662-663, 1994. [PubMed: 7959749] [Full Text: https://doi.org/10.1006/geno.1994.1332]
Srivastava, M. Genomic structure and expression of the human gene encoding cytochrome b(561), an integral protein of the chromaffin granule membrane. J. Biol. Chem. 270: 22714-22720, 1995. [PubMed: 7559396] [Full Text: https://doi.org/10.1074/jbc.270.39.22714]
van den Berg, M. P., Almomani, R., Biaggioni, I., van Faassen, M., van der Harst, P., Sillje, H. H. W., Leach, I. M., Hemmelder, M. H., Navis, G., Luijckx, G. J., de Brouwer, A. P. M., Venselaar, H., Verbeek, M. M., van der Zwaag, P. A., Jongbloed, J. D. H., van Tintelen, J. P., Wevers, R. A., Kema, I. P. Mutations in CYB561 causing a novel orthostatic hypotension syndrome. Circ. Res. 122: 846-854, 2018. [PubMed: 29343526] [Full Text: https://doi.org/10.1161/CIRCRESAHA.117.311949]
Vargas, J. D., Herpers, B., McKie, A. T., Gledhill, S., McDonnell, J., van den Heuvel, M., Davies, K. E., Ponting, C. P. Stromal cell-derived receptor 2 and cytochrome b561 are functional ferric reductases. Biochim. Biophys. Acta 1651: 116-123, 2003. [PubMed: 14499595] [Full Text: https://doi.org/10.1016/s1570-9639(03)00242-5]