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Cited by 18Sexual Differentiation and DisordersAdrenal Hormones and DisordersGenomic variations and chromosomal abnormalities

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

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Chen, Wuyan, Xu, Zhi, Nishitani, Miki, Van Ryzin, Carol, McDonnell, Nazli B., Merke, Deborah P.·2012·Human Genetics
DOI 10.1007/s00439-012-1217-8PMC PMC3493742
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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.

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  • Occasionally a breakpoint occurs in the TNX genes, leading to complete deletion of C4B and CYP21A2, and a TNXB/TNXA chimeric gene.

    “Occasionally a breakpoint occurs in the TNX genes, leading to complete deletion of C4B and CYP21A2, and a TNXB/TNXA chimeric gene (149,150,189).”

    From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [149]

    The Discussion (page not provided) describes a subset of patients with complete CYP21A2 deletion extending into TNXB and producing a TNXA/TNXB chimera. It reports decreased total C4 copy number with chimeras, but does not say that C4B is completely deleted or specify a breakpoint within the TNX genes. It also names the chimera TNXA/TNXB, rather than TNXB/TNXA. (LLM, conf=0.87)

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Research works printed but not linked: 14

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Authors
Chen, W., Xu, Z., Nishitani, M., Van Ryzin, C., McDonnell, N. B., & Merke, D. P.
Affiliations
  • National Institute on Aging (US)
  • National Institutes of Health (US)
Corresponding author
Merke, Deborah P.
ORCID
Venue
Human Genetics
Publisher
Springer Science and Business Media LLC
Published
2012-08-12
Volume
131
Issue
12
Pages
1889-1894
ISSN
  • 0018-7348 (ISSN-L)
  • 0340-6717
  • 1432-1203
DOI
10.1007/s00439-012-1217-8
PMC
PMC3493742
OpenAlex
W1982825915
Cited by
18
References
8
Citations by year
2026: 2 · 2025: 3 · 2024: 1 · 2021: 2 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 1 · 2013: 2
FWCI
0.51
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Human Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (Z99CL999999)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
congenital adrenal hyperplasia, 21-hydroxylase deficiency, CYP21A2 mutations, complement C4, copy number variation, autoimmune disease susceptibility
MeSH terms
Adolescent, Adrenal Hyperplasia, Congenital, Adult, Child, Child, Preschool, Complement C4, Female, Humans, Male, Middle Aged, Mutation, Nuclear Proteins, Steroid 21-Hydroxylase, Cohort Studies, Autoimmunity, Protein Serine-Threonine Kinases, Gene Dosage, Tenascin, DNA Copy Number Variations

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