ArticleThe Journal of experimental medicine2000
Deficiencies of human complement component C4A and C4B and heterozygosity in length variants of RP-C4-CYP21-TNX (RCCX) modules in caucasians. The load of RCCX genetic diversity on major histocompatibility complex-associated disease.
Article in The Journal of experimental medicine, 2000. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed, 187 citations in OpenAlex.
- Clinical and Biochemical Phenotype Across the Genotypic Spectrum of 21-hydroxylase Deficiency in 457 Individuals.The Journal of clinical endocrinology and metabolism · 2026Article
- A Case of Salt-Wasting Congenital Adrenal Hyperplasia Caused by a Rare Intronic Variant in theInternational journal of molecular sciences · 2025Article
- Unique Case Report: A Rare Association of 21-Hydroxylase Deficiency with Triple X Karyotype.Genes · 2025Article
- Genetics in Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency and Clinical Implications.Journal of the Endocrine Society · 2025Review
- High clinical utility of long-read sequencing for precise diagnosis of congenital adrenal hyperplasia in 322 probands.Human genomics · 2025Article
- Severe Clinical Manifestation of a Salt Wasting Form of Congenital Adrenal Hyperplasia Harboring a Complex Genotype.Case reports in endocrinology · 2025Article
- Exploration of the potential of genomic editing in the treatment of congenital adrenal hyperplasia.Frontiers in endocrinology · 2025Review
- Novel rapid molecular diagnosis methods for comprehensive genetic analysis of 21-hydroxylase deficiency.Orphanet journal of rare diseases · 2024Article
- Low C4A copy numbers and higher HERV gene insertion contributes to increased risk of SLE, with absence of association with disease phenotype and disease activity.Immunologic research · 2024Article
- Review
- Molecular basis and genetic testing strategies for diagnosing 21-hydroxylase deficiency, including CAH-X syndrome.Annals of pediatric endocrinology & metabolism · 2023Article
- The complement system and human autoimmune diseases.Journal of autoimmunity · 2023Review
- Salt-wasting congenital adrenal hyperplasia phenotype as a result of the TNXA/TNXB chimera 1 (CAH-X CH-1) and the pathogenic IVS2-13A/C > G in CYP21A2 gene.Hormones (Athens, Greece) · 2023Article
- Low copy numbers of complementAnnals of the rheumatic diseases · 2023Article
- PseudogeneGenes · 2023Article
- The pathogenic p.Gln319Ter variant is not causing congenital adrenal hyperplasia when inherited in one of the duplicated CYP21A2 genes.Frontiers in endocrinology · 2023Article
- Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis.NPJ genomic medicine · 2022Article
- Congenital Adrenal Hyperplasia-Current Insights in Pathophysiology, Diagnostics, and Management.Endocrine reviews · 2022Review
- Congenital Adrenal Hyperplasia and Ehlers-Danlos Syndrome.Frontiers in endocrinology · 2022Review
- Human Complement C4B Allotypes and Deficiencies in Selected Cases With Autoimmune Diseases.Frontiers in immunology · 2021Article
16 more citing papers are in PubMed but not listed here.
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9 authors at 2 institutions in 1 country.
Funding
Abstract
The complement component C4 genes located in the major histocompatibility complex (MHC) class III region exhibit an unusually complex pattern of variations in gene number, gene size, and nucleotide polymorphism. Duplication or deletion of a C4 gene always concurs with its neighboring genes serine/threonine nuclear protein kinase RP, steroid 21-hydroxylase (CYP21), and tenascin (TNX), which together form a genetic unit termed the RCCX module. A detailed molecular genetic analysis of C4A and C4B and RCCX modular arrangements was correlated with immunochemical studies of C4A and C4B protein polymorphism in 150 normal Caucasians. The results show that bimodular RCCX has a frequency of 69%, whereas monomodular and trimodular RCCX structures account for 17.0 and 14.0%, respectively. Three quarters of C4 genes harbor the endogenous retrovirus HERV-K(C4). Partial deficiencies of C4A and C4B, primarily due to gene deletions and homoexpression of C4A proteins, have a combined frequency of 31.6%. This is probably the most common variation of gene dosage and gene size in human genomes. The seven RCCX physical variants create a great repertoire of haplotypes and diploid combinations, and a heterozygosity frequency of 69.4%. This phenomenon promotes the exchange of genetic information among RCCX constituents that is important in homogenizing the structural and functional diversities of C4A and C4B proteins. However, such length variants may cause unequal, interchromosomal crossovers leading to MHC-associated diseases. An analyses of the RCCX structures in 22 salt-losing, congenital adrenal hyperplasia patients revealed a significant increase in the monomodular structure with a long C4 gene linked to the pseudogene CYP21A, and bimodular structures with two CYP21A, which are likely generated by recombinations between heterozygous RCCX length variants.
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