Molecular Genetics of the Fourth Component of Human Complement and Steroid 21‐Hydroxylase

Carroll, Michael; Belt, Katharina; Pálsdóttir, Ástrídur; Yu, Yung

doi:10.1111/j.1600-065x.1985.tb01144.x

Cited by 73 publications

(40 citation statements)

References 86 publications

(83 reference statements)

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“…It is also interesting to note that this isozyme in contrast to other cytochrome P-450 forms cannot be induced by drugs known to induce human drug metabolism (Eichelbaum etal., 1986b). With the exception of steroid 21-hydroxylase (Carroll et al, 1985), a polycylic aromatic hydrocarbon (PAH) inducible (Hildebrand et al, 1985) and a phenobarbitone inducible (Phillips et al, 1985) cytochrome P-450 the chromosomal location of the various human cytochrome P-450 isozymes is not known. Steroid 21-hydroxylase is located on the short arm of human chromosome 6.…”

Section: Discussionmentioning

confidence: 99%

“…Steroid 21-hydroxylase is located on the short arm of human chromosome 6. In this case it was possible through the deletion of C4 A/B to map precisely the gene for steroid 21-hydroxylase (Carroll et al, 1985). Using a human cDNA clone and human-rodent hybrids a phenobarbitone inducible human cytochrome P-450 has been mapped to chromosome 19 (19 p 13.2-qter) (Phillips et al, 1985) (Julier et al, 1985;Tippett & Kaplan, 1985).…”

Section: Discussionmentioning

confidence: 99%

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Chromosomal assignment of human cytochrome P‐450 (debrisoquine/sparteine type) to chromosome 22.

Eichelbaum¹,

Mp²,

Dengler³

et al. 1987

Brit J Clinical Pharma

102

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1 In order to determine on which chromosome the gene controlling human cytochrome P-450 (debrisoquine/sparteine type) is located a linkage study of polymorphic sparteine oxidation (PSO) to various polymorphic markers was carried out. 2 Positive information for linkage between PSO and the P1 blood group was obtained with a maximal LOD-score of LOD = 3.35 for both male and female recombination fraction estimates of Om = of = 0.0. 3 The P1 blood group has been recently mapped to the long arm of chromosome 22. Thus it can be concluded that the gene controlling human cytochrome P-450 (debrisoquine/ sparteine) is situated on the long arm of chromosome 22 in close vicinity to P1.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Chromosomal assignment of human cytochrome P‐450 (debrisoquine/sparteine type) to chromosome 22.

Eichelbaum¹,

Mp²,

Dengler³

et al. 1987

Brit J Clinical Pharma

102

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“…The 5' C4 fragments were mapped relative to the 12-and 3.5-kb Kpn I fragments characteristic for the 5' ends of the C4A and the C4B genes (5). The correlation of these fiagments with the two forms ofthe C4B genes has been established by hybridization of Kpn I digested DNA with the cDNA probe pALU-7, which yields a 7.5-kb band for the long C4 genes and an 8.5-kb band for the short C4B gene (26,39 Two different forms of C4B deletions were detected in family EM. (Fig.…”

Section: Introductionmentioning

confidence: 99%

Polymorphism of the human complement C4 and steroid 21-hydroxylase genes. Restriction fragment length polymorphisms revealing structural deletions, homoduplications, and size variants.

Schneider¹,

Carroll²,

Alper³

et al. 1986

J. Clin. Invest.

236

113

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Several autoimmune disorders as well as congenital adrenal hyperplasia (CAH) are either associated or closely linked with genetic variants of the fourth component of complement (C4A and C4B) and the enzyme steroid 21-hydroxylase (21-OH). These proteins are encoded by genes that are located downstream from the genes for complement proteins, C2 and factor B (BF) between HLA-B and -DR in the major histocompatibility complex (MHC). Previous studies of variants and null alleles were based on electrophoretic mobility ofC4 protein and linkage with disease phenotypes. These data did not permit analysis of the basis for the observed null alleles and duplicated variants. We studied this region ofthe MHC in 126 haplotypes for a structural analysis of the four adjacent loci, C4A, 21-OHA, C4B, and 21-OHB. About half of the C4 genes typed as C4 null are deleted and several unrecognized homoduplicated C4 alleles were detected.Hence the frequencies of different C4 structural variants must be recalculated based on a direct analysis of the genes. Analysis of the C4/21-OH genes of patients with the classical (salt-wasting) form of CAH showed that some involve a deletion of the C4B and 21-OHB genes; whereas for two only the 21-OHB gene is deleted, i.e., the C4B gene is present. Together, these data provide a better understanding of the mechanisms generating and importance of deleted C4 and 21-OH null alleles in human disease.

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“…The gene encoding C4, the fourth component of complement, has been duplicated recently in several mammalian species (31). In humans there are two functional C4 genes that are each polymorphic and show differences in the hemolytic activity of their products (2). In mouse, the duplicate gene has diverged further: its product no longer functions in the complement pathway, and its expression is regulated by androgen (27).…”

mentioning

confidence: 99%

Molecular genetics of androgen-dependent and -independent expression of mouse sex-limited protein.

Stavenhagen¹,

Loreni²,

Hemenway³

et al. 1987

Mol. Cell. Biol.

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Genes of the mouse S locus encoding C4 (the fourth component complement) and Slp (sex-limited protein) show extensive homology but are distinct in their function and regulation. In some mouse strains, such as B10.D2, Slp is androgen regulated, whereas in others, such as B10.W7R, expression of Slp is constitutive. We have previously shown that the B10.W7R strain has multiple Slp genes. In this report, we present the structure of the single C4 and four Slp genes of the B10.W7R S locus and compare the upstream flanking regions by partial sequence analysis and function in transfection assays. Of the four Slp genes, three (Slpw7.A, Slpw7.B, and Slpw7.C) have upstream and promoter regions very similar to those of C4. The fourth Slp gene (Slpw7.D) is instead virtually identical to the androgen-regulated allele (Slpd from the B10.D2 mouse) in upstream regions. In particular, far-upstream sequences from both Slpd and Slpw7.D render the bacterial chloramphenicol acetyltransferase gene hormonally responsive upon transfection into mammary carcinoma cell lines. The upstream sequences between 2 to 3 kilobases of the Slp promoter initiate transcription from multiple sites when fused proximal to the chloramphenicol acetyltransferase gene, and these transcripts are threefold more abundant in the presence of androgen. This behavior is similar for Slpd and Slpw7.D, which suggests that Slpw7.D may be androgen regulated but that this is masked in vivo by constitutive expression of the other Slp genes. Nonhomologous recombination is implicated not only in expanding the copy number of C4 and Slp genes in the B10.W7R mouse but also in creating hybrid genes with regulatory features of C4 and structural features of Slp.

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Molecular Genetics of the Fourth Component of Human Complement and Steroid 21‐Hydroxylase

Cited by 73 publications

References 86 publications

Chromosomal assignment of human cytochrome P‐450 (debrisoquine/sparteine type) to chromosome 22.

Chromosomal assignment of human cytochrome P‐450 (debrisoquine/sparteine type) to chromosome 22.

Polymorphism of the human complement C4 and steroid 21-hydroxylase genes. Restriction fragment length polymorphisms revealing structural deletions, homoduplications, and size variants.

Molecular genetics of androgen-dependent and -independent expression of mouse sex-limited protein.

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