RFXANK, the regulatory factor X-associated ankyrin-containing protein, is a crucial subunit of the heterotrimeric RFX complex. This complex is involved in the regulation of the transcription of major histocompatibility complex class II (MHC II) molecules in antigen-presenting cells, which is essential for the proper functioning of the immune system [3,5,6,7,8,9]. It also interacts with RFX7 and caspase-2, potentially playing roles in natural killer cell-mediated immunity, neuron development, and MHC II gene regulation [2,4].

Mutations in the RFXANK gene account for over 70% of known patients with MHC II deficiency worldwide. Homozygous loss-of-function mutations in RFXANK can cause bare lymphocyte syndrome (BLS) type II, and the associated phenotype has been expanded to include progressive neurodegenerative disease, with MRI showing global cerebral and cerebellar atrophy [1,3,6]. Patients with RFXANK mutations often present with later onset and diagnosis compared to those with RFX5 mutations in MHC-II deficiency [5].

In conclusion, RFXANK is essential for the regulation of MHC II molecule transcription, playing a key role in immune function. The discovery of its association with neurodegenerative disease through studies of patients with RFXANK mutations broadens our understanding of its functions. Understanding RFXANK's role can potentially aid in early diagnosis, prognosis refinement, and treatment strategies for MHC-II deficiency-related diseases [1,3,5].

References:

1. Alharby, Essa, Obaid, Mona, Elamin, Mohammed A O, Alasmari, Ali, Almontashiri, Naif A M. 2021. Progressive Ataxia and Neurologic Regression in RFXANK-Associated Bare Lymphocyte Syndrome. In Neurology. Genetics, 7, e586. doi:10.1212/NXG.0000000000000586. https://pubmed.ncbi.nlm.nih.gov/33855173/

2. Gao, Jun, Xu, Chao. 2019. Structural basis for the recognition of RFX7 by ANKRA2 and RFXANK. In Biochemical and biophysical research communications, 523, 263-266. doi:10.1016/j.bbrc.2019.12.059. https://pubmed.ncbi.nlm.nih.gov/31864703/

3. Cai, Yu Qing, Zhang, HangHu, Wang, Xiang Zhi, Shu, YingYing, Tang, Lan Fang. 2020. A Novel RFXANK Mutation in a Chinese Child With MHC II Deficiency: Case Report and Literature Review. In Open forum infectious diseases, 7, ofaa314. doi:10.1093/ofid/ofaa314. https://pubmed.ncbi.nlm.nih.gov/32875002/

4. Forsberg, Jeremy, Li, Xinge, Akpinar, Birce, Zhivotovsky, Boris, Olsson, Magnus. 2018. A caspase-2-RFXANK interaction and its implication for MHC class II expression. In Cell death & disease, 9, 80. doi:10.1038/s41419-017-0144-y. https://pubmed.ncbi.nlm.nih.gov/29362422/

5. Gulec Koksal, Zeynep, Bilgic Eltan, Sevgi, Topyildiz, Ezgi, Karakoc Aydiner, Elif, Baris, Safa. 2024. MHC Class II Deficiency: Clinical, Immunological, and Genetic Insights in a Large Multicenter Cohort. In The journal of allergy and clinical immunology. In practice, 12, 2490-2502.e6. doi:10.1016/j.jaip.2024.06.046. https://pubmed.ncbi.nlm.nih.gov/38996837/

6. Abolnezhadian, Farhad, Dehghani, Razieh, Dehnavi, Sajad, Khodadadi, Ali, Shohan, Mojtaba. . A novel mutation in RFXANK gene and low B cell count in a patient with MHC class II deficiency: a case report. In Immunologic research, 68, 225-231. doi:10.1007/s12026-020-09141-9. https://pubmed.ncbi.nlm.nih.gov/32578129/

7. Mousavi Khorshidi, Mohadese Sadat, Seeleuthner, Yoann, Chavoshzadeh, Zahra, Shahrooei, Mohammad, Parvaneh, Nima. 2023. Clinical, Immunological, and Genetic Findings in Iranian Patients with MHC-II Deficiency: Confirmation of c.162delG RFXANK Founder Mutation in the Iranian Population. In Journal of clinical immunology, 43, 1941-1952. doi:10.1007/s10875-023-01562-z. https://pubmed.ncbi.nlm.nih.gov/37584719/

8. Wiszniewski, Wojciech, Fondaneche, Marie-Claude, Louise-Plence, Pascale, Fischer, Alain, Lisowska-Grospierre, Barbara. 2003. Novel mutations in the RFXANK gene: RFX complex containing in-vitro-generated RFXANK mutant binds the promoter without transactivating MHC II. In Immunogenetics, 54, 747-55. doi:. https://pubmed.ncbi.nlm.nih.gov/12618906/

9. Chakraborty, Madhumita, Sengupta, Amitava, Bhattacharya, Dipankar, Banerjee, Subrata, Chakrabarti, Abhijit. 2010. DNA binding domain of RFX5: interactions with X-box DNA and RFXANK. In Biochimica et biophysica acta, 1804, 2016-24. doi:10.1016/j.bbapap.2010.07.009. https://pubmed.ncbi.nlm.nih.gov/20637319/