MS4A1 gene

The MS4A1 gene (MS4A1-stands for "Membrane Spanning 4-Domains A1" ), is a protein coding gene located on chromosome 11q12.2. Alternative splicing of this gene results in two transcript variants encoding the same protein.

The MS4A1 gene encodes the CD20 protein. It belongs to a superordinate protein family whose members are characterized by common structural features and similar intron/exon splice boundaries. They exhibit a unique expression pattern in hematopoietic cells and non-lymphoid tissues. The CD20 protein is a B lymphocyte-specific membrane protein that plays a role in the development and differentiation of B cells into plasma cells. It is also used in this capacity for diagnostic purposes.

CD20 plays a role in the regulation of cellular calcium influx required for B lymphocyte development, differentiation, and activation (Tedder TF et al. 1985).Here, it functions as a component of a store-operated calcium (SOC) channel that promotes calcium influx following activation by the B cell receptor-BCR-(Polyak MJ et al. 2008).

Diseases associated with MS4A1 includeimmunodeficiency syndrome , immunodeficiency, common variable, 5 or CVID 5, mutation in MS4A1 (CD20).

The introduction of anti-CD20 monoclonal antibodies such as rituximab, ofatumumab, or obinutuzumab has significantly improved the therapy of B-cell malignancies, although the exact physiological role and regulation of CD20 remains unclear. Moreover, CD20 expression varies markedly between different B-cell malignancies, patients with the same malignancy, and even between intraclonal subpopulations in a single patient (Pavlasova G et al. 2020).

Several epigenetic (EZH2, HDAC1/2, HDAC1/4, HDAC6, complex Sin3A-HDAC1) factors and transcription factors (USF, OCT1/2, PU.1, PiP, ELK1, ETS1, SP1, NFκB, FOXO1, CREM, SMAD2/3) regulating CD20 expression (encoded by MS4A1) have been characterized. CD20 has also been shown to interact with numerous other surface proteins on B cells (such as CD40, MHCII, CD53, CD81, CD82, and CBP). Current efforts are aimed at combining monoclonal antibodies against CD20 with BCR signaling inhibitors targeting BTK or PI3K (ibrutinib, acalabrutinib, idelalisib, duvelisib) or BH3 mimetics (venetoclax).

1. Pavlasova G et al. (2020) The regulation and function of CD20: an "enigma" of B-cell biology and targeted therapy. Haematologica 105:1494-1506.
2. Polyak MJ et al (2008) CD20 homo-oligomers physically associate with the B cell antigen receptor. Dissociation upon receptor engagement and recruitment of phosphoproteins and calmodulin-binding proteins. J Biol Chem 283:18545-1852.
3. Tedder TF et al (1985) The B cell surface molecule B1 is functionally linked with B cell activation and differentiation. J Immunol 135:973-979. Li H et al (2003) Store-operated cation entry mediated by CD20 in membrane rafts. J Biol Chem 278:42427-4234.