Inherited incomplete deficiency of the fourth component of complement (C4) determined by a gene not linked to human histocompatibility leukocyte antigens.

Muir, Walter; Hedrick, Stephen M.; Alper, Chester A.; Ratnoff, Oscar D.; Schacter, Bernice; Wisnieski, Jeffrey J.

doi:10.1172/jci111564

Cited by 21 publications

(17 citation statements)

References 22 publications

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“…The kindred has been described previously (1)(2)(3)(4). Incomplete C4 deficiency and dysfunctional Cl inhibitor are uniformly associated in 11 members of a five-family kindred spanning three generations.…”

Section: Methodsmentioning

confidence: 99%

“…We have described a large kindred with hereditary reduced levels of the fourth component of complement (C4) (1). C4 metabolic tumover studies failed to demonstrate hypercatabolism of C4 and appeared to be compatible with C4 hyposynthesis, even though C4 structural alleles are intact in affected kindred members (2).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we found that after a 15-min incubation, -50% of serum Cl inhibitor in kindred members with decreased C4 levels did not complex with and inhibit Clr (3). Despite this failure, Cl inhibitor function, measured as inhibition of CIs and as the ability to form an SDS-stable complex with Cls, was normal in affected kindred members' sera ( 1,3 ). In addition, approximately half of the Cl inhibitor molecules in affected members' sera appeared to be relatively resistant to cleavage by trypsin between the reactive center P1 Arg 44 and P1' Thr"5 residues.…”

Section: Introductionmentioning

confidence: 99%

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Unique C1 inhibitor dysfunction in a kindred without angioedema. II. Identification of an Ala443-->Val substitution and functional analysis of the recombinant mutant protein.

Zahedi¹,

Bissler²,

Davis³

et al. 1995

J. Clin. Invest.

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We have determined the cause of an unusual Cl inhibitor abnormality in a large kindred. We previously found that half of serum Cl inhibitor molecules in affected kindred members are normal. The other half complexed with Cls but showed little complex formation with Clr. These molecules also appeared to be relatively resistant to digestion by trypsin. Taken together, the findings suggested that members of this kindred are heterozygous for an unusual Cl inhibitor mutation. Sequencing of genomic DNA from the kindred revealed that thymine has replaced cytosine in the codon for Ala443 (P2 residue) in one Cl inhibitor allele, resulting in substitution with a Val residue. To test the effect of this substitution, a mutant Cl inhibitor containing Ala"3--Val was constructed by site-directed mutagenesis and expressed in COS-1 cells. Both the Ala'3--Val mutant and the wild-type Cl inhibitor complexed completely with Cls, kallikrein, and coagulation Factor XIIa after incubation at 37°C for 60 min. In contrast, the mutant inhibitor failed to complex completely with Clr under the same conditions. Time course analysis showed that the ability of the mutant to complex with Cls is also impaired: although it complexed completely in 60 min, the rate of complex formation during a 0-60-min incubation was decreased compared with wild-type Cl inhibitor. The mutant inhibitor also formed a complex with trypsin, a serine protease that cleaves, and is not inhibited by, wild-type Cl inhibitor. The Ala"3-Val mutation therefore converts Cl inhibitor from a substrate to an inhibitor of trypsin. These studies emphasize the role of the P2 residue in the determination of target protease specificity. (J. Clin. Invest. 1995. 95:1299-1305

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Unique C1 inhibitor dysfunction in a kindred without angioedema. II. Identification of an Ala443-->Val substitution and functional analysis of the recombinant mutant protein.

Zahedi¹,

Bissler²,

Davis³

et al. 1995

J. Clin. Invest.

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“…It is possible that low C4 levels drive from a defective structural gene or an abnormal genetic control over transcriptional or posttranscriptional events that influence C4 production. Recently, incomplete C4 deficiency has been described in a family the locus of which was not linked to the HLA system and in which the affected kindred had a heterozygous defective C1 inhibitor allele, with a P2 Ala 443 →Val substitution, which did not complex with and did not inhibit C1r but complexed with and inhibited C1s [8][9][10][11]. The molecular basis of as to how mutation in C1 inhibitor caused subnormal C4 levels is not known.…”

Section: Introductionmentioning

confidence: 99%

Molecular Heterogeneity of Second and Fourth Components of Complement and Their Genes in Systemic Sclerosis and Association of HLA Alleles A1, B8 and DR3 with Limited and DR5 with Diffuse Systemic Sclerosis

Venneker¹,

Hoogen²,

Meegen³

et al. 1998

Exp Clin Immunogenet

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Deficiency of the complement component C4 at the functional, protein and gene level and deficiency of complement component C2 at the functional level were investigated and HLA analysis was performed on patients with limited and diffuse systemic sclerosis (SSc). One of the patients with limited SSc (n = 15) had subnormal C4, 1 subnormal C2 and 1 subnormal C4 and C2 activities; the latter patient had HLA alleles A11;B35;Dw1 associated with type II C2 deficiency and therefore most likely had a defect at the C2 locus. One of the patients with diffuse SSC (n = 12) had subnormal C4 and 1 subnormal C4 and C2 activities. C2 deficiencies in patients other than the one with the haplotype associated with C2 deficiency appeared not to be determined by the gene at the C2 locus. The incidence of partial C2 deficiency in a normal Caucasian population is reported to be 16 in 10,000, and that of partial C4 deficiency also appears to be very low. The percentages of C4A*Q0 and C4B*Q0 alleles in normal controls (n = 45) were within the reported range. Seven patients with limited SSc (n = 14) had one or two C4A*Q0 alleles and 2 with diffuse SSc (n = 13) had one C4A*Q0 allele. Thus, the incidence of C4A*Q0 was higher than normal in limited SSc and within the normal range in diffuse SSc. The two-sided Fisher’s exact test applied on these data revealed that the association of C4A*Q0 with limited SSc did not reach a significant level (p = 0.10). Two of the 3 patients with limited SSc, who had two C4A*Q0 alleles, carried a heterozygous C4A-21-hydroxylase A (OHA) gene segment deletion as detected by Southern blotting. There was no correlation between the subnormal activity of C4 and the occurrence of one or two C4A*Q0 (and C4A-21-OHA segment deletion). HLA alleles A1, B8 and DR3 (p = 0.002) were associated with limited SSc (n = 23) and DR5(w11) (p = 0.018) with diffuse SSc (n = 17).

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“…We recently described a 2-generation kindred in which development of SLE in the proband led to the discovery of a unique hereditary deficiency of C4 (18). In contrast with other C4-deficient families, C4 was not totally absent in affected members of this kindred.…”

mentioning

confidence: 99%

Metabolism of C4 and linkage analysis in a kindred with hereditary incomplete C4 deficiency

Wisnieski

Nathanson

Anderson

et al. 1987

Arthritis & Rheumatism

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We studied a kindred in which C4 deficiency had been discovered. Unlike families with total absence of C4, in this kindred C4 deficiency was found to be incomplete, autosomal dominant, not caused by null alleles, and not associated with a high incidence of systemic lupus erythematosus. The deficient state was caused by hyposynthesis of C4, not by hypercatabolism. The locus for incomplete C4 deficiency was not closely linked to the major histocompatibility complex. The abnormal autosomal dominant allele is, apparently, rare, and how it causes decreased synthesis of C4 is unknown.

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Inherited incomplete deficiency of the fourth component of complement (C4) determined by a gene not linked to human histocompatibility leukocyte antigens.

Cited by 21 publications

References 22 publications

Unique C1 inhibitor dysfunction in a kindred without angioedema. II. Identification of an Ala443-->Val substitution and functional analysis of the recombinant mutant protein.

Unique C1 inhibitor dysfunction in a kindred without angioedema. II. Identification of an Ala443-->Val substitution and functional analysis of the recombinant mutant protein.

Molecular Heterogeneity of Second and Fourth Components of Complement and Their Genes in Systemic Sclerosis and Association of HLA Alleles A1, B8 and DR3 with Limited and DR5 with Diffuse Systemic Sclerosis

Metabolism of C4 and linkage analysis in a kindred with hereditary incomplete C4 deficiency

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