Physiological functions of UPR components in mouse models and their genetic association with human disease
| Gene | Factors that regulate expression | Phenotypes of knockout mouse model | Genetic association with human diseases | References |
| IRE1α | N.A. | (1) Embryonic lethality at E12.5 due to liver hypoplasia; (2) Liver deletion: hypolipidemia | (1) Human somatic cancers | Zhang et al., 2005, 2011; Greenman et al., 2007 |
| XBP1s | XBP1s and ATF6α | (1) Embryonic lethality at E13.5 due to liver hypoplasia; (2) Liver deletion: hypolipidemia; (3) Intestinal epithelial cell deletion: enteritis; (4) Pancreatic acinar cell deletion: extensive pancreas regeneration; (5) Pancreatic β cell deletion: hyperglycemia; (6) Neuron deletion: leptin resistance | (1) Inflammatory bowel disease; (2) Schizophrenia in the Japanese population; (3) Bipolar disorder; (4) Ischemic stroke | Kakiuchi et al., 2003b, 2004; Kaser et al., 2008; Yilmaz et al., 2010 |
| ATF6α | N.A. | (1) Susceptible to pharmacologically induced ER stress | (1) Type 2 diabetes and pre-diabetic traits; (2) Increased plasma cholesterol levels | Chu et al., 2007; Wu et al., 2007; Meex et al., 2009 |
| CREBH | PPARα, HNF4α, and ATF6α | (1) Hypoferremia and spleen iron sequestration; (2) Hyperlipidemia; (3) Liver knockdown: fasting hyperglycemia | (1) Extreme hypertriglyceridemia | Zhang et al., 2006; Vecchi et al., 2009; J.H. Lee et al., 2011 |
| PERK | N.A. | (1) Neonatal hyperglycemia | (1) Wolcott-Rallison syndrome; (2) Supranuclear palsy | Delépine et al., 2000; Höglinger et al., 2011 |
| ATF4 | CHOP | (1) Delayed bone formation; (2) Severe fetal anemia; (3) Increased insulin sensitivity; (4) Defects in long-term memory | N.A. | Elefteriou et al., 2006; Costa-Mattioli et al., 2007; Yamaguchi et al., 2008 |
| CHOP | ATF4 and ATF6α | (1) Protected from pharmacologically induced ER stress; (2) Protected from type 2 diabetes; (3) Protected from atherosclerosis; (4) Protected from leukodystrophy Pelizaeus-Merzbacher disease | (1) Early-onset type 2 diabetes in Italians | Oyadomari et al., 2002; Marciniak et al., 2004; Silva et al., 2005; Gragnoli, 2008; Song et al., 2008 |
| WFS1 | XBP1s | (1) Diabetes due to insufficient insulin secretion; (2) Growth retardation | (1) Wolfram syndrome; (2) Risk of type 2 diabetes in Japanese and European populations | Karasik et al., 1989; Inoue et al., 1998; Ishihara et al., 2004; Mita et al., 2008 |
| ORMDL3 | N.A. | N.A. | (1) Ulcerative colitis; (2) Risk of childhood asthma | Hjelmqvist et al., 2002; Breslow et al., 2010; McGovern et al., 2010 |
| Grp78 (BiP) | ATF6α and ATF4 | (1) Embryonic lethality at E3.5 due to impaired embryo peri-implantation; (2) Liver deletion: simultaneous liver damage and hepatic steatosis | (1) Bipolar disorder | Kakiuchi et al., 2005; Luo et al., 2006; R. Ye et al., 2010 |
| SIL1 | XBP1s | (1) Adult-onset ataxia with cerebellar Purkinje cell loss | (1) Marinesco-Sjogren syndrome; (2) Alzheimer’s disease | Tyson and Stirling, 2000; Anttonen et al., 2005; Zhao et al., 2005, 2010 |
| Grp94 | XBP1s, ATF6α, and ATF4 | (1) Embryonic lethality at E7; (2) B cell deletion: reduced antibody production; (3) Bone marrow deletion: hematopoietic stem cell expansion | (1) Bipolar disorder | Kakiuchi et al., 2007; Mao et al., 2010 |
| P58 IPK | XBP1s and ATF6α | (1) Diabetes | N.A. | Ladiges et al., 2005 |
| Calnexin | XBP1s and ATF6α | (1) Postnatal death; (2) Motor disorder | N.A. | Denzel et al., 2002 |
| Calreticulin | XBP1s and ATF6α | (1) Embryonic lethality at E14.5 | (1) A case of schizophrenia | Aghajani et al., 2006 |
| Seleno-protein S | N.A. | (1) Disturbed redox homeostasis in the liver and cataract development in eyes | (1) Inflammatory response; (2) Non-small cell lung cancer | Hart et al., 2011; Kasaikina et al., 2011 |
| Gene | Factors that regulate expression | Phenotypes of knockout mouse model | Genetic association with human diseases | References |
| IRE1α | N.A. | (1) Embryonic lethality at E12.5 due to liver hypoplasia; (2) Liver deletion: hypolipidemia | (1) Human somatic cancers | Zhang et al., 2005, 2011; Greenman et al., 2007 |
| XBP1s | XBP1s and ATF6α | (1) Embryonic lethality at E13.5 due to liver hypoplasia; (2) Liver deletion: hypolipidemia; (3) Intestinal epithelial cell deletion: enteritis; (4) Pancreatic acinar cell deletion: extensive pancreas regeneration; (5) Pancreatic β cell deletion: hyperglycemia; (6) Neuron deletion: leptin resistance | (1) Inflammatory bowel disease; (2) Schizophrenia in the Japanese population; (3) Bipolar disorder; (4) Ischemic stroke | Kakiuchi et al., 2003b, 2004; Kaser et al., 2008; Yilmaz et al., 2010 |
| ATF6α | N.A. | (1) Susceptible to pharmacologically induced ER stress | (1) Type 2 diabetes and pre-diabetic traits; (2) Increased plasma cholesterol levels | Chu et al., 2007; Wu et al., 2007; Meex et al., 2009 |
| CREBH | PPARα, HNF4α, and ATF6α | (1) Hypoferremia and spleen iron sequestration; (2) Hyperlipidemia; (3) Liver knockdown: fasting hyperglycemia | (1) Extreme hypertriglyceridemia | Zhang et al., 2006; Vecchi et al., 2009; J.H. Lee et al., 2011 |
| PERK | N.A. | (1) Neonatal hyperglycemia | (1) Wolcott-Rallison syndrome; (2) Supranuclear palsy | Delépine et al., 2000; Höglinger et al., 2011 |
| ATF4 | CHOP | (1) Delayed bone formation; (2) Severe fetal anemia; (3) Increased insulin sensitivity; (4) Defects in long-term memory | N.A. | Elefteriou et al., 2006; Costa-Mattioli et al., 2007; Yamaguchi et al., 2008 |
| CHOP | ATF4 and ATF6α | (1) Protected from pharmacologically induced ER stress; (2) Protected from type 2 diabetes; (3) Protected from atherosclerosis; (4) Protected from leukodystrophy Pelizaeus-Merzbacher disease | (1) Early-onset type 2 diabetes in Italians | Oyadomari et al., 2002; Marciniak et al., 2004; Silva et al., 2005; Gragnoli, 2008; Song et al., 2008 |
| WFS1 | XBP1s | (1) Diabetes due to insufficient insulin secretion; (2) Growth retardation | (1) Wolfram syndrome; (2) Risk of type 2 diabetes in Japanese and European populations | Karasik et al., 1989; Inoue et al., 1998; Ishihara et al., 2004; Mita et al., 2008 |
| ORMDL3 | N.A. | N.A. | (1) Ulcerative colitis; (2) Risk of childhood asthma | Hjelmqvist et al., 2002; Breslow et al., 2010; McGovern et al., 2010 |
| Grp78 (BiP) | ATF6α and ATF4 | (1) Embryonic lethality at E3.5 due to impaired embryo peri-implantation; (2) Liver deletion: simultaneous liver damage and hepatic steatosis | (1) Bipolar disorder | Kakiuchi et al., 2005; Luo et al., 2006; R. Ye et al., 2010 |
| SIL1 | XBP1s | (1) Adult-onset ataxia with cerebellar Purkinje cell loss | (1) Marinesco-Sjogren syndrome; (2) Alzheimer’s disease | Tyson and Stirling, 2000; Anttonen et al., 2005; Zhao et al., 2005, 2010 |
| Grp94 | XBP1s, ATF6α, and ATF4 | (1) Embryonic lethality at E7; (2) B cell deletion: reduced antibody production; (3) Bone marrow deletion: hematopoietic stem cell expansion | (1) Bipolar disorder | Kakiuchi et al., 2007; Mao et al., 2010 |
| P58 IPK | XBP1s and ATF6α | (1) Diabetes | N.A. | Ladiges et al., 2005 |
| Calnexin | XBP1s and ATF6α | (1) Postnatal death; (2) Motor disorder | N.A. | Denzel et al., 2002 |
| Calreticulin | XBP1s and ATF6α | (1) Embryonic lethality at E14.5 | (1) A case of schizophrenia | Aghajani et al., 2006 |
| Seleno-protein S | N.A. | (1) Disturbed redox homeostasis in the liver and cataract development in eyes | (1) Inflammatory response; (2) Non-small cell lung cancer | Hart et al., 2011; Kasaikina et al., 2011 |
N.A., not applicable.