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

被引:0
作者
Wuyan Chen
Zhi Xu
Miki Nishitani
Carol Van Ryzin
Nazli B. McDonnell
Deborah P. Merke
机构
[1] National Institute on Aging,Laboratory of Clinical Investigation
[2] Clinical Center,National Institutes of Health
[3] The Eunice Kennedy Shriver National Institute of Child Health and Human Development,Program in Developmental Endocrinology and Genetics (PDEGEN), National Institutes of Health
[4] National Institute on Aging,Clinical Research Branch
[5] National Institutes of Health,undefined
来源
Human Genetics | 2012年 / 131卷
关键词
Copy Number Variation; Congenital Adrenal Hyperplasia; CYP21A2 Gene; CYP21A2 Genotype; Congenital Adrenal Hyperplasia Patient;
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学科分类号
摘要
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. In this study, we performed comprehensive genetic analysis of the RP-C4-CYP21-TNX (RCCX) region 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. We found that 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, a common mutation associated with the classic form of CAH, 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). In conclusion, 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.
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页码:1889 / 1894
页数:5
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