Sec61a1 encodes a subunit of the translocation machinery of protein biosynthesis at the endoplasmic reticulum (ER), playing a central role in the process of protein translocation across the ER membrane [2]. Mutations in Sec61a1 are associated with several diseases, highlighting its biological importance in normal physiological function [1,2,4,5,7,8].

Mutations in Sec61a1 have been linked to autosomal dominant tubulointerstitial kidney disease (ADTKD), a condition characterized by tubular damage and interstitial fibrosis leading to end-stage renal disease [1,4,8]. A Sec61a1 variant has also been associated with autosomal dominant polycystic liver disease, where mutant Sec61a1 led to enhanced proteasomal degradation and impaired biosynthesis of polycystin-2 [2]. In multiple myeloma, circ_Sec61a1 was found to accelerate disease progression by modulating the miR-660-5p/CDK6 axis [3]. High Sec61a1 expression predicts poor outcome in acute myeloid leukemia, and is associated with increased cell-growth-related signaling pathways [5]. In Buruli ulcer, SEC61A1 was identified as an essential factor for mycolactone-dependent apoptosis in human premonocytic THP-1 cells [6]. A digenic inheritance of IL-36RA and SEC61A1 mutations underlies generalized pustular psoriasis with hypogammaglobulinemia [7]. A novel SEC61A1 variant was associated with hypoaldosteronism [8]. In colon adenocarcinoma, an E2F1-mediated MNX1-AS1-miR-218-5p-SEC61A1 feedback loop contributes to disease progression [9].

In conclusion, Sec61a1 is crucial for protein translocation at the ER. Research on Sec61a1-related diseases such as ADTKD, polycystic liver disease, multiple myeloma, acute myeloid leukemia, Buruli ulcer, generalized pustular psoriasis, and colon adenocarcinoma has provided insights into its role in disease pathogenesis. Understanding Sec61a1 function in these disease models may offer potential therapeutic targets for treatment.

References:

1. Devuyst, Olivier, Olinger, Eric, Weber, Stefanie, Rampoldi, Luca, Bleyer, Anthony J. 2019. Autosomal dominant tubulointerstitial kidney disease. In Nature reviews. Disease primers, 5, 60. doi:10.1038/s41572-019-0109-9. https://pubmed.ncbi.nlm.nih.gov/31488840/

2. Schlevogt, Bernhard, Schlieper, Vincent, Krader, Jana, Nedvetsky, Pavel I, Krahn, Michael P. 2022. A SEC61A1 variant is associated with autosomal dominant polycystic liver disease. In Liver international : official journal of the International Association for the Study of the Liver, 43, 401-412. doi:10.1111/liv.15493. https://pubmed.ncbi.nlm.nih.gov/36478640/

3. Luo, Zimian, Yin, Yafei, Tan, Xiaojun, Chao, Zhi, Xia, Hong. 2021. Circ_SEC61A1 contributes to the progression of multiple myeloma cells via regulating miR-660-5p/CDK6 axis. In Leukemia research, 113, 106774. doi:10.1016/j.leukres.2021.106774. https://pubmed.ncbi.nlm.nih.gov/35030455/

4. Espino-Hernández, Mar, Palma Milla, Carmen, Vara-Martín, Julia, González-Granado, Luis I. 2020. De novo SEC61A1 mutation in autosomal dominant tubulo-interstitial kidney disease: Phenotype expansion and review of literature. In Journal of paediatrics and child health, 57, 1305-1307. doi:10.1111/jpc.15148. https://pubmed.ncbi.nlm.nih.gov/33185949/

5. Ji, Guo, Yang, Xiaofei, Li, Jun. 2024. High SEC61A1 expression predicts poor outcome of acute myeloid leukemia. In Open medicine (Warsaw, Poland), 19, 20240944. doi:10.1515/med-2024-0944. https://pubmed.ncbi.nlm.nih.gov/38584833/

6. Kawashima, Akira, Kiriya, Mitsuo, En, Junichiro, Goto, Masamichi, Suzuki, Koichi. 2022. Genome-wide screening identified SEC61A1 as an essential factor for mycolactone-dependent apoptosis in human premonocytic THP-1 cells. In PLoS neglected tropical diseases, 16, e0010672. doi:10.1371/journal.pntd.0010672. https://pubmed.ncbi.nlm.nih.gov/35939511/

7. Almutairi, Abduarahman, Amin, Maha M, Rashwan, Mohamed A M, Platt, Craig D, Sobh, Ali. 2022. Digenic inheritance of IL-36RA and SEC61A1 mutations underlies generalized pustular psoriasis with hypogammaglobulinemia. In Clinical immunology (Orlando, Fla.), 235, 108930. doi:10.1016/j.clim.2022.108930. https://pubmed.ncbi.nlm.nih.gov/35063669/

8. Karpman, Diana, Lindström, Martin L, Möller, Mattias, Fogo, Agnes B, Elfving, Maria. 2024. Hypoaldosteronism due to a novel SEC61A1 variant successfully treated with fludrocortisone. In Clinical kidney journal, 17, sfae213. doi:10.1093/ckj/sfae213. https://pubmed.ncbi.nlm.nih.gov/39135939/

9. Ye, Yaqun, Gu, Binbin, Wang, Yi, Shen, Sudan, Huang, Wei. 2018. E2F1-mediated MNX1-AS1-miR-218-5p-SEC61A1 feedback loop contributes to the progression of colon adenocarcinoma. In Journal of cellular biochemistry, 120, 6145-6153. doi:10.1002/jcb.27902. https://pubmed.ncbi.nlm.nih.gov/30362161/