Dgkh-KO Mouse

DGKH, which codes for the eta (η) isoform of diacylglycerol kinase, is involved in the phosphoinositol pathway. It plays a role in various biological processes, and its genetic variants are associated with multiple diseases [3,5,6,7].

In Philadelphia chromosome-like acute lymphoblastic leukemia (ALL), genomic alterations in DGKH can activate kinase signaling, contributing to this high-risk subset of ALL [1].

In hepatocellular carcinoma (HCC), DGKH is a crucial oncometabolic regulator. It promotes mTOR signaling by producing phosphatidic acid, augmenting aggressive features such as cancer stemness, therapy resistance, and metastasis. In an immunocompetent mouse model, depletion of Dgkh reduced tumor burden and related hallmarks [2].

In bipolar disorder (BD), DGKH is a replicated risk gene. Risk variant carriers show altered gene expression in peripheral blood and fibroblasts. The risk haplotype is associated with increased amygdala volume in BD patients, and the A allele of DGKH (a putative risk allele) is associated with higher openness to experience, a premorbid personality trait of BD [3,5,7].

In diabetic cognitive dysfunction, high glucose inhibits the demethylation modification of Dgkh by ALKBH5, downregulating Dgkh and leading to tau hyperphosphorylation in hippocampal neurons. Overexpression of Dgkh in diabetic rats ameliorated tau hyperphosphorylation and cognitive dysfunction [4].

In Parkinson's disease, DGKH expression levels are lower in both the substantia nigra and peripheral blood mononuclear cells of patients, suggesting its potential as a diagnostic biomarker [8].

In summary, DGKH is involved in multiple biological processes and is associated with various diseases. Studies, especially those using in vivo models in HCC and diabetic cognitive dysfunction, have revealed its role in disease-related mechanisms. Its association with diseases like ALL, BD, and Parkinson's disease further emphasizes its importance in understanding disease etiology and potentially developing new therapeutic strategies.

References:

1. Tasian, Sarah K, Loh, Mignon L, Hunger, Stephen P. 2017. Philadelphia chromosome-like acute lymphoblastic leukemia. In Blood, 130, 2064-2072. doi:10.1182/blood-2017-06-743252. https://pubmed.ncbi.nlm.nih.gov/28972016/

2. Loh, Jia Jian, Ng, Kai Yu, Huang, Ianto Bosheng, Yun, Jing-Ping, Ma, Stephanie. 2024. DGKH-mediated phosphatidic acid oncometabolism as a driver of self-renewal and therapy resistance in HCC. In Hepatology (Baltimore, Md.), , . doi:10.1097/HEP.0000000000001158. https://pubmed.ncbi.nlm.nih.gov/39663958/

3. Kittel-Schneider, Sarah, Lorenz, Carina, Auer, Joyce, Weißflog, Lena, Reif, Andreas. 2016. DGKH genetic risk variant influences gene expression in bipolar affective disorder. In Journal of affective disorders, 198, 148-57. doi:10.1016/j.jad.2016.03.041. https://pubmed.ncbi.nlm.nih.gov/27016658/

4. Qu, Minli, Zuo, Linhui, Zhang, Mengru, Li, Changjun, Wu, Jing. 2023. High glucose induces tau hyperphosphorylation in hippocampal neurons via inhibition of ALKBH5-mediated Dgkh m6A demethylation: a potential mechanism for diabetic cognitive dysfunction. In Cell death & disease, 14, 385. doi:10.1038/s41419-023-05909-7. https://pubmed.ncbi.nlm.nih.gov/37385994/

5. Kittel-Schneider, S, Wobrock, T, Scherk, H, Gruber, O, Reif, A. 2014. Influence of DGKH variants on amygdala volume in patients with bipolar affective disorder and schizophrenia. In European archives of psychiatry and clinical neuroscience, 265, 127-36. doi:10.1007/s00406-014-0513-9. https://pubmed.ncbi.nlm.nih.gov/24958494/

6. Weißflog, Lena, Becker, Nils, Bossert, Nelli, Kittel-Schneider, Sarah, Reif, Andreas. 2016. Expressional profile of the diacylglycerol kinase eta gene DGKH. In European archives of psychiatry and clinical neuroscience, 267, 445-454. doi:10.1007/s00406-016-0695-4. https://pubmed.ncbi.nlm.nih.gov/27085324/

7. Matsumoto, Yoshihiko, Suzuki, Akihito, Shirata, Toshinori, Goto, Kaoru, Otani, Koichi. 2018. Implication of the DGKH genotype in openness to experience, a premorbid personality trait of bipolar disorder. In Journal of affective disorders, 238, 539-541. doi:10.1016/j.jad.2018.06.031. https://pubmed.ncbi.nlm.nih.gov/29936393/

8. Asad Samani, Leila, Ghaedi, Kamran, Majd, Ahmad, Peymani, Maryam, Etemadifar, Masoud. 2023. Coordinated modification in expression levels of HSPA1A/B, DGKH, and NOTCH2 in Parkinson's patients' blood and substantia nigra as a diagnostic sign: the transcriptomes' relationship. In Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 44, 2753-2761. doi:10.1007/s10072-023-06738-4. https://pubmed.ncbi.nlm.nih.gov/36973590/