[1][2] CNVs are segments of DNA that vary in copy number compared to a reference genome and play a significant role in human phenotypic variation and disease development.
The RCCX cluster consists of one or more modules each having a series of genes close to each other: serine/threonine kinase 19 (STK19), complement 4 (C4), steroid 21-hydroxylase (CYP21), and tenascin-X (TNX).
[2][7] Each copy of the C4 gene, due to five adjacent nucleotide substitutions cause four amino acid changes and immunological subfunctionalization (different functions related to the immune system),[7] can be of one of two types: C4A and C4B.
[14][15][16][17] RCCX modules exhibit a high degree of linkage disequilibrium, meaning that genes are inherited together more frequently than would be expected by chance.
By increasing the activation of the mitogen-activated protein kinase (MAPK) cascade, STK19 ultimately influences cellular processes such as cell growth, proliferation, and differentiation.
[3] The RCCX module may be involved in developing autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis: the C4A gene may be associated with an increased risk of systemic lupus erythematosus, while the C4B gene may be associated with an increased risk of rheumatoid arthritis.
[26][27][28] The HERV-K retrovirus within the C4 gene has also been associated with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, probably because retrovirus may activate the C4 gene, leading to increased production of C4 proteins, which can contribute to autoimmune responses, and can probably lead to neuroinflammation, and increased risk of developing diseases such as schizophrenia and bipolar disorder.
The exact molecular mechanisms through which alterations or deficiencies in the TNXB gene or its impaired function lead to these conditions (the EDS and the CAH-X syndrome) are not fully understood yet but are believed to be related to defects in extracellular matrix organization and cell adhesion processes mediated by tenascin-X protein.
According to the hypothesis, these variations contribute to the development of autoimmune disorders, such as lupus and rheumatoid arthritis, as well as psychiatric conditions, such as anxiety and depression.