Cd46, also known as membrane cofactor protein (MCP), is a ubiquitously expressed complement regulatory protein. It serves as a cofactor for serine protease factor I to cleave and inactivate C3b and C4b deposited on host cells, thus playing a crucial role in preventing complement-mediated "self-attack" [1,3]. Additionally, it is involved in human reproduction, autophagy, modulating T cell activation and effector functions, and is part of the intracellular complement system (complosome) [1]. It is also a receptor for 11 pathogens, earning it the title "pathogen magnet" [1].

Mutations in Cd46 predispose to atypical hemolytic uremic syndrome (aHUS) with low penetrance. In a study of a large single family, individuals carrying a rare, heterozygous Cd46 gene splice-site mutation showed reduced CD46-dependent T cell mitochondrial adaptation. Diseased mutation carriers had lower peripheral regulatory T cell (Treg) frequencies and carried potentially epistatic, private rare variants in other inborn errors of immunity (IEI)-associated proinflammatory genes, suggesting that low Treg and rare non-Cd46 immune-gene variants may contribute to clinically manifest Cd46 haploinsufficiency-associated immune-dysregulation [2].

In conclusion, Cd46 is a multifunctional protein involved in complement regulation, immune modulation, and pathogen interactions. The study of Cd46-related mutations in families, similar to what could be modeled in KO/CKO mouse models, helps to understand its role in diseases like aHUS and immune-dysregulation, providing insights into the underlying mechanisms and potential therapeutic targets.

References:

1. Liszewski, M Kathryn, Atkinson, John P. 2021. Membrane cofactor protein (MCP; CD46): deficiency states and pathogen connections. In Current opinion in immunology, 72, 126-134. doi:10.1016/j.coi.2021.04.005. https://pubmed.ncbi.nlm.nih.gov/34004375/

2. Meyer, Benedikt J, Kunz, Natalia, Seki, Sayuri, Hess, Christoph, Recher, Mike. 2023. Immunologic and Genetic Contributors to CD46-Dependent Immune Dysregulation. In Journal of clinical immunology, 43, 1840-1856. doi:10.1007/s10875-023-01547-y. https://pubmed.ncbi.nlm.nih.gov/37477760/

3. Cardone, J, Le Friec, G, Kemper, C. 2011. CD46 in innate and adaptive immunity: an update. In Clinical and experimental immunology, 164, 301-11. doi:10.1111/j.1365-2249.2011.04400.x. https://pubmed.ncbi.nlm.nih.gov/21488871/