Alternative titles; symbols
HGNC Approved Gene Symbol: HYOU1
Cytogenetic location: 11q23.3 Genomic coordinates (GRCh38) : 11:119,044,188-119,057,205 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q23.3 | ?Immunodeficiency 59 and hypoglycemia | 233600 | Autosomal recessive | 3 |
Astrocytes retain cell viability, even in extreme ischemia, and proliferate in damaged brain (Petito et al., 1990; Janeczko, 1991). Rat astrocytes exposed to hypoxia followed by reoxygenation were reported to release increased amounts of interleukin-6 (147620) that could promote neuronal survival in ischemic brain (Maeda et al., 1994). Kuwabara et al. (1996) observed a 150-kD protein, called oxygen-regulated protein (ORP150) by them, in the endoplasmic reticulum (ER) of cultured astrocytes that was induced specifically by hypoxia and not by other stimuli.
Ikeda et al. (1997) reported the cloning of human and rat ORP150 cDNAs from hypoxia-treated human astrocytoma U373 cells and rat astrocytes, respectively. The full-length 4,503-bp human cDNA contains a 2,997-bp open reading frame predicted to encode a polypeptide of 999 amino acids with a calculated molecular mass of 111,330 Da. The deduced amino acid sequences of human and rat ORP150 exhibit high similarity (over 90% identity) to each other. The first 32 residues represent the signal peptide necessary for secretion. The C-terminal KNDEL sequence resembles KDEL, a motif found in ER-resident proteins, suggesting that ORP150 resides in the ER. The N-terminal half of ORP150 has a modest similarity to the ATPase domain of numerous HSP70 family sequences (see 140550). Northern blot analysis revealed a marked similarity of expression between ORP150 and GRP78 (138120) in U373 cells during hypoxia stress. (The GRP78 protein is produced in cultured rat astrocytes exposed to hypoxia or hypoxia/reoxygenation.) They also found that ORP150 mRNA was highly expressed in the liver and pancreas, whereas little expression was observed in the kidney and brain, similarly to the expression pattern of GRP78. Ikeda et al. (1997) proposed that ORP150 plays an important role in protein folding and secretion in the ER, perhaps as a molecular chaperone in concert with other GRPs, to cope with environmental stress.
Stumpf (2023) mapped the HYOU1 gene to chromosome 11q23.3 based on an alignment of the HYOU1 sequence (GenBank AK314178) with the genomic sequence (GRCh38).
Tamatani et al. (2001) found that although ORP150 was sparingly upregulated in neurons from human brain undergoing ischemic stress, there was robust induction in astrocytes. Cultured neurons overexpressing ORP150 were resistant to hypoxemic stress, whereas astrocytes with inhibited ORP150 expression were more vulnerable. Mice with targeted neuronal overexpression of ORP150 had smaller strokes compared with controls. Neurons with increased ORP150 demonstrated suppressed caspase-3-like activity and enhanced brain-derived neurotrophic factor (BDNF) (113505) under hypoxia signaling. Tamatani et al. (2001) concluded that ORP150 is an integral participant in ischemic cytoprotective pathways.
Ozawa et al. (2001) demonstrated coexpression, colocalization, and coimmunoprecipitation of ORP150 and vascular endothelial growth factor (VEGF; 192240) in the ER of macrophages within the neovasculature of human wound granulation tissue. In vitro, inhibition of ORP150 resulted in retention of VEGF within the ER, whereas overexpression of ORP150 promoted the secretion of VEGF into hypoxic culture supernatants, indicating that ORP150 may participate in VEGF transport to the cytoplasm. In wounds of diabetic mice, overexpression of ORP150 resulted in accelerated repair and closure; suppression of ORP150 delayed repair. Ozawa et al. (2001) concluded that ORP150 plays a role in the promotion of angiogenesis, and more generally acts as a molecular chaperone under hypoxic conditions to facilitate protein transport and processing in the ER.
Two members of the HSP70 family are required for protein biogenesis in the yeast endoplasmic reticulum: Lhs1 (homologous to HYOU1) and Kar2 (homologous to HSPA5, or BiP; 138120). Steel et al. (2004) found that Lhs1 and Kar2 specifically interacted to couple, and coordinately regulate, their respective activities. Lhs1 stimulated Kar2 by providing a specific nucleotide exchange activity, whereas Kar2 reciprocally activated the Lhs1 ATPase. In yeast, the 2 ATPase activities are coupled, and their coordinated regulation is essential for normal function in vivo.
Zhao et al. (2010) showed that overexpression of Hyou1 prevented ER stress and rescued neurodegeneration of Purkinje cells in Sil1 (608005) -/- mice, whereas decreasing expression of Hyou1 exacerbated these phenotypes. Purkinje cells from the caudal lobules of the cerebellum from Sil1 -/- mice typically do not show signs of ER stress; however, decreased expression of Hyou1 in these cells resulted in signs of ER stress, ubiquitin-positive inclusions, and death. Zhao et al. (2010) suggested that HYOU1 and SIL1 have partially redundant functions as BiP nucleotide exchange factors in Purkinje cells.
In a 45-year-old woman with combined immunodeficiency and recurrent stress-induced hypoglycemia (IMD59; 233600), Haapaniemi et al. (2017) identified compound heterozygosity for missense mutations in the HYOU1 gene (A419P, 601746.0001 and Y231H, 601746.0002).
In a 45-year-old woman with combined immunodeficiency and recurrent stress-induced hypoglycemia (IMD59; 233600), Haapaniemi et al. (2017) identified compound heterozygosity for missense mutations in the HOU1 gene: a chr11:118,922,614C-G transversion (chr11.118,922,614C-G, GRCh37), resulting in an ala419-to-pro (R419P) substitution, and an A-G transition (chr11.118,924,936A-G, GRCh37), resulting in a tyr231-to-his (Y231H; 601746.0002) substitution. Both occurred at conserved residues within the ATPase domain. The patient's unaffected parents were each heterozygous for one of the mutations. Analysis in HEK293 cells showed altered binding profiles for both mutants, resulting in ectopic protein binding. RNA sequencing of patient fibroblasts showed a strikingly different transcriptional profile compared to controls, and the transcriptome suggested enhanced protein synthesis, glucose metabolism, and redox enzyme transcription in patient cells. Electron microscopy of patient neutrophils revealed increased numbers of mitochondria as well as high reactive oxygen species production compared to controls. In the XF Cell Mito Stress test, patient fibroblasts performed consistently on the low-normal end, but significant alterations were not present.
For discussion of the chr11:118,924,936A-G transition in the HYOU1 gene (chr11.118,924,936A-G, GRCh37), resulting in a tyr231-to-his (Y231H) substitution, that was found in compound heterozygous state in a patient with immunodeficiency-59 with hypoglycemia (IMD59; 233600) by Haapaniemi et al. (2017), see 601746.0001.
Haapaniemi, E. M., Fogarty, C. L., Keskitalo, S., Katayama, S., Vihinen, H., Ilander, M., Mustjoki, S., Krjutskov, K., Lehto, M., Hautala, T., Eriksson, O., Jokitalo, E., Velagapudi, V., Varjosalo, M., Seppanen, M., Kere, J. Combined immunodeficiency and hypoglycemia associated with mutations in hypoxia upregulated 1. (Letter) J. Allergy Clin. Immun. 139: 1391-1393, 2017. [PubMed: 27913302] [Full Text: https://doi.org/10.1016/j.jaci.2016.09.050]
Ikeda, J., Kaneda, S., Kuwabara, K., Ogawa, S., Kobayashi, T., Matsumoto, M., Yura, T., Yanagi, H. Cloning and expression of cDNA encoding the human 150 kDa oxygen-regulated protein, ORP150. Biochem. Biophys. Res. Commun. 230: 94-99, 1997. [PubMed: 9020069] [Full Text: https://doi.org/10.1006/bbrc.1996.5890]
Janeczko, K. The proliferative response of S-100 protein-positive glial cells to injury in the neonatal rat brain. Brain Res. 564: 86-90, 1991. [PubMed: 1777824] [Full Text: https://doi.org/10.1016/0006-8993(91)91355-5]
Kuwabara, K., Matsumoto, M., Ikeda, J., Hori, O., Ogawa, S., Maeda, Y., Kitagawa, K., Imuta, N., Kinoshita, T., Stern, D. M., Yanagi, H., Kamada, T. Purification and characterization of a novel stress protein, the 150-kDa oxygen-regulated protein (ORP150), from cultured rat astrocytes and its expression in ischemic mouse brain. J. Biol. Chem. 271: 5025-5032, 1996. [PubMed: 8617779] [Full Text: https://doi.org/10.1074/jbc.271.9.5025]
Maeda, Y., Matsumoto, M., Hori, O., Kuwabara, K., Ogawa, S., Yan, S. D., Ohtsuki, T., Kinoshita, T., Kamada, T., Stern, D. M. Hypoxia/reoxygenation-mediated induction of astrocyte interleukin 6: a paracrine mechanism potentially enhancing neuron survival. J. Exp. Med. 180: 2297-2308, 1994. [PubMed: 7964502] [Full Text: https://doi.org/10.1084/jem.180.6.2297]
Ozawa, K., Kondo, T., Hori, O., Kitao, Y., Stern, D. M., Eisenmenger, W., Ogawa, S., Ohshima, T. Expression of the oxygen-regulated protein ORP150 accelerates wound healing by modulating intracellular VEGF transport. J. Clin. Invest. 108: 41-50, 2001. [PubMed: 11435456] [Full Text: https://doi.org/10.1172/JCI11772]
Petito, C. K., Morgello, S., Felix, J. C., Lesser, M. L. The two patterns of reactive astrocytosis in postischemic rat brain. J. Cereb. Blood Flow Metab. 10: 850-859, 1990. [PubMed: 2211878] [Full Text: https://doi.org/10.1038/jcbfm.1990.141]
Steel, G. J., Fullerton, D. M., Tyson, J. R., Stirling, C. J. Coordinated activation of Hsp70 chaperones. Science 303: 98-101, 2004. [PubMed: 14704430] [Full Text: https://doi.org/10.1126/science.1092287]
Stumpf, A. M. Personal Communication. Baltimore, Md. 11/17/2023.
Tamatani, M., Matsuyama, T., Yamaguchi, A., Mitsuda, N., Tsukamoto, Y., Taniguchi, M., Che, Y. H., Ozawa, K., Hori, O., Nishimura, H., Yamashita, A., Okabe, M., Yanagi, H., Stern, D. M., Ogawa, S., Tohyama, M. ORP150 protects against hypoxia/ischemia-induced neuronal death. Nature Med. 7: 317-323, 2001. [PubMed: 11231630] [Full Text: https://doi.org/10.1038/85463]
Zhao, L., Rosales, C., Seburn, K., Ron, D., Ackerman, S. L. Alteration of the unfolded protein response modifies neurodegeneration in a mouse model of Marinesco-Sjogren syndrome. Hum. Molec. Genet. 19: 25-35, 2010. [PubMed: 19801575] [Full Text: https://doi.org/10.1093/hmg/ddp464]