Diaph1, also known as mammalian diaphanous-1, is a formin that regulates actin dynamics, signal transduction, and metabolic functions [1-3, 5-9]. It is involved in multiple pathways, such as the RAGE/DIAPH1 signaling pathway which is linked to atherosclerosis, and it also plays a role in maintaining cellular homeostasis by regulating inter-organelle contact between mitochondria and sarco/endoplasmic reticulum (SR/ER) [1,3,4]. Genetic models like knockout mice are valuable for studying Diaph1.

In gene knockout mouse models, global deletion of Diaph1 in Ldlr -/- mice significantly attenuates atherosclerosis, with lower plasma and liver concentrations of cholesterol and triglyceride, suggesting its role in lipid metabolism and atherosclerosis progression [2,3,4]. In Diaph1 knockout mice, primordial germ cell proliferation is inhibited, and gonadal development is affected, leading to decreased fertility due to disrupted sex hormone production [7]. Also, homozygous loss of DIAPH1 in humans and in CRISPR-Cas9 knockout of DIAPH1 in healthy donor PBMCs results in combined immunodeficiency, mitochondrial dysfunction, and defects in T-cell activation, adhesion, and microtubule-organizing center repositioning [5,6].

In conclusion, Diaph1 is crucial for actin-related functions, inter-organelle contact, and various biological processes. Its knockout models have revealed its significant contributions to diseases like atherosclerosis, immunodeficiency, and reproductive-related disorders, providing insights into disease mechanisms and potential therapeutic targets.

References:

1. Yepuri, Gautham, Ramirez, Lisa M, Theophall, Gregory G, Shekhtman, Alexander, Ramasamy, Ravichandran. 2023. DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress. In Nature communications, 14, 6900. doi:10.1038/s41467-023-42521-x. https://pubmed.ncbi.nlm.nih.gov/37903764/

2. Senatus, Laura, Egaña-Gorroño, Lander, López-Díez, Raquel, Ramasamy, Ravichandran, Schmidt, Ann Marie. 2023. DIAPH1 mediates progression of atherosclerosis and regulates hepatic lipid metabolism in mice. In Communications biology, 6, 280. doi:10.1038/s42003-023-04643-2. https://pubmed.ncbi.nlm.nih.gov/36932214/

3. Ramasamy, Ravichandran, Shekhtman, Alexander, Schmidt, Ann Marie. 2023. RAGE/DIAPH1 and atherosclerosis through an evolving lens: Viewing the cell from the "Inside - Out". In Atherosclerosis, , 117304. doi:10.1016/j.atherosclerosis.2023.117304. https://pubmed.ncbi.nlm.nih.gov/39492058/

4. Ramasamy, Ravichandran, Shekhtman, Alexander, Schmidt, Ann Marie. 2023. RAGE/DIAPH1 and atherosclerosis through an evolving lens: Viewing the cell from the "Inside - Out". In Atherosclerosis, 394, . doi:10.1016/j.atherosclerosis.2023.117304. https://pubmed.ncbi.nlm.nih.gov/39131441/

5. Azizoglu, Zehra Busra, Babayeva, Royala, Haskologlu, Zehra Sule, Baris, Safa, Eken, Ahmet. 2024. DIAPH1-Deficiency is Associated with Major T, NK and ILC Defects in Humans. In Journal of clinical immunology, 44, 175. doi:10.1007/s10875-024-01777-8. https://pubmed.ncbi.nlm.nih.gov/39120629/

6. Kaustio, Meri, Nayebzadeh, Naemeh, Hinttala, Reetta, Uusimaa, Johanna, Saarela, Janna. 2021. Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction. In The Journal of allergy and clinical immunology, 148, 599-611. doi:10.1016/j.jaci.2020.12.656. https://pubmed.ncbi.nlm.nih.gov/33662367/

7. Zhao, Xin, Fan, Chunbiao, Qie, Tongtong, Yan, Wenlong, Yu, Haiquan. 2024. Diaph1 knockout inhibits mouse primordial germ cell proliferation and affects gonadal development. In Reproductive biology and endocrinology : RB&E, 22, 82. doi:10.1186/s12958-024-01257-z. https://pubmed.ncbi.nlm.nih.gov/39010074/