title: Complement component 4 copy number variation and CYP21A2 genotype associations in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
abstract: 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.
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, USA. wuyanchen.nia@gmail.com
authors.forename: Wuyan
authors.initials: W
authors.lastname: Chen
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xu
authors.forename: Miki
authors.initials: M
authors.lastname: Nishitani
authors.forename: Carol
authors.initials: C
authors.lastname: Van Ryzin
authors.forename: Nazli B
authors.initials: NB
authors.lastname: McDonnell
authors.forename: Deborah P
authors.initials: DP
authors.lastname: Merke
mesh_terms: D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000201:enzymology / Q000235:genetics* / Q000276:immunology; D000328:Adult; D015551:Autoimmunity / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003181:Complement C4 / Q000235:genetics*; D056915:DNA Copy Number Variations; D005260:Female; D018628:Gene Dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D013255:Steroid 21-Hydroxylase / Q000235:genetics*; D019063:Tenascin / Q000235:genetics
chemical_list: D003181:Complement C4; D009687:Nuclear Proteins; D019063:Tenascin; C081865:tenascin X; C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase; D017346:Protein Serine-Threonine Kinases; C087996:STK19 protein, human