Complement component 4 copy number variation and CYP21A2 genotype associations in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Abstract

Background Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder of cortisol biosynthesis caused by CYP21A2 mutations. An increase in gene copy number variation (CNV) exists at the CYP21A2 locus. CNV of C4, a neighboring gene that encodes complement component 4, is associated with autoimmune disease susceptibility. Methods Comprehensive genetic analysis of the RCCX (RP-C4-CYP21-TNX) region was conducted in 127 unrelated 21-OHD patients (100 classic, 27 nonclassic). C4 copy number was determined by Southern blot. C4 CNV and serum C4 levels were evaluated in relation to CYP21A2 mutations and relevant phenotypes. Results The most common CYP21A2 mutation associated with the nonclassic form of CAH, V281L, was associated with high C4 copy number (p=7.13×10−16). Large CYP21A2 deletion was associated with low C4 copy number (p=1.61×10−14). Monomodular RCCX with a short C4 gene, a risk factor for autoimmune disease, was significantly less frequent in CAH patients compared to population estimates (2.8 vs. 10.6%; p=1.08×10−4). Conclusions CAH patients have increased C4 CNV, with mutation-specific associations that may be protective for autoimmune disease. The study of CYP21A2 in relation to neighboring genes provides insight into the genetics of CNV hotspots, an important determinant of human health.

Increased Risk of Autoimmune Disorders in 21-Hydroxylase Deficiency: A Swedish Population-Based National Cohort Study

“…High levels of C4 would conversely lead to a lower susceptibility to autoimmune disorders. High C4 was especially noted in patients with NC 21OHD (V281L), thereby indicating protection against autoimmunity [16]. This result is not congruent with our findings but may be partly explained by other factors discussed below.…”

“…They were studied as part of a larger study of patients with DSD, including women with CAH, and were then found to be increased compared with controls, but very few details were reported [6]. Another study of 127 patients with 21OHD reported autoimmune disorders in 4 of them (autoimmune thyroiditis, n = 2; IBD, n = 1; juvenile rheumatoid arthritis, n = 1) [16]. This latter study assessed the complement compound 4, C4 copy number variation among the patients with different CYP21A2 genotypes and found that 21OHD was associated with very low or very high C4 copy number.…”

“…Thus, it could be suspected that autoimmune disorders are more prevalent in 21OHD, but very little has been reported, and if mentioned, little or no details of the autoimmune disorders have been provided [6, 16, 17]. The aims of the current study were to investigate the prevalence of autoimmune disorders in all individuals with 21OHD in Sweden and to assess whether the outcomes differed between the sexes, among age groups, and for the different phenotypes and genotypes.…”

Genetics of Congenital Adrenal Hyperplasia

“…Copy number variation (CNV) of C4, CYP21, and TNX is widely found in humans; in patients with CAH, a greater C4 CNV with mutation-specific associations has been shown to possibly confer protection for autoimmune disease. 13 Due to the high degree of sequence homology between CYP21A2 and its pseudogene, recombination occurs. Approximately 70% of CYP21A2 disease causing mutations are pseudogene derived variants due to gene conversion, the transfer of deleterious pseudogene mutations to the active CYP21A2 gene,., 14 and approximately 25-30% are chimeric genes due to large deletions.…”

Detection of mutations in theCYP21A2gene: genotype-phenotype correlation in Slovenian couples with conceiving problems

“…[ 26 ] found that a mutation in the CYP21A2 gene results not only in 21-OH deficiency but also in a variable copy count of the C4 gene. To clarify, the C4 gene encodes a homonymous protein, involved in classic complement activation [ 26 ]. In our study, we did not find a statistically significant association between autoimmunity and our studied mutations.…”