Complement Component 4b Deficiency

A number sign (#) is used with this entry because C4B deficiency is caused by mutation in the C4B gene (120820).

Clinical Features

Partial deficiency of C4 was found in 3 persons during a screening of 42,000 healthy Japanese (Torisu et al., 1970).

Of 26 patients with autoimmune chronic active hepatitis beginning in childhood, Vergani et al. (1985) found low C4 in 18 (69%) and low C3 serum levels in 5 (19%). Associated characteristics indicated a defect in synthesis of C4 and a genetic basis thereof was indicated by the fact that C4 phenotyping in 20 patients and in 26 parents showed that 90% and 81%, respectively, had null allotypes at either the C4A or C4B locus compared with 59% in controls.

Homozygous deficiency of C4A (614380) is associated with systemic lupus erythematosus (152700) and with type I diabetes mellitus; homozygous deficiency of C4B is associated with susceptibility to bacterial meningitis (Winkelstein, 1987).

In 3 African-American patients with systemic lupus erythematosus (SLE; 152700), Wilson and Perez (1988) found complete deficiency of plasma C4B.

Lhotta et al. (1990) stated that only 17 cases of complete deficiency of C4 had been described. They described a patient with complete deficiency and renal disease, first presenting as severe Henoch-Schonlein purpura with renal involvement at the age of 17. Six years later, he developed hypertension and nephrotic syndrome, requiring hemodialysis followed by cadaveric kidney graft. After 2 years of uncomplicated course, the patient suffered a recurrence of his primary disease in the grafted kidney.

Molecular Genetics

Awdeh et al. (1981) analyzed C4 types in relatives of a C4-deficient proband and provided evidence that the deficiency results from homozygosity for a rare, double-null haplotype. The family contained persons with 1, 2, 3, or 4 expressed C4 genes, and the mean serum C4 levels roughly reflected the number of structural genes present.

To evaluate the molecular basis of the C4-null phenotypes, Partanen et al. (1988) used Southern blotting techniques to analyze genomic DNA from 23 patients with systemic lupus erythematosus (SLE; 152700) and from healthy controls. They confirmed the earlier findings of high frequencies of C4-null phenotypes and of HLA-B8,DR3 antigens. In addition, they found that among the patients most of both the C4A (120810)- and C4B-null phenotypes resulted from gene deletions. Among the controls, only the C4A-null phenotypes were predominantly the result of gene deletions. In all SLE cases, the C4 gene deletions extended also to a closely linked pseudogene, CYP21A (613815). Altogether, 52% of the patients and 26% of the controls carried a C4/CYP21A deletion. Partanen et al. (1989) found that deletions in 6p involving the C4 and CYP21 loci fell within the range of 30 to 38 kb, as determined by pulsed-field gel electrophoresis. Because the deletion sizes in most other gene clusters were more heterogeneous, the results suggested to Partanen et al. (1989) the involvement of a specific mechanism in the generation of C4/CYP21 deletions.

In a 9-year-old girl with SLE and complete C4 deficiency, Welch et al. (1990) found uniparental isodisomy 6. The girl had 2 identical chromosome 6 haplotypes from the father and none from the mother.

Fasano et al. (1992) studied a 7-year-old patient with recurrent sinopulmonary infections in whom the rare C4A*Q0,B*Q0 double-null haplotype was shown to be due to a recombination event within the C4B locus in the mother, who possessed a C4A*Q0,B*1 haplotype and a C4A*3,B*1 haplotype. By segregation analysis, they mapped the recombination to a region 3-prime to the unique 6.4-kb TaqI restriction fragment of the maternal C4B locus.

Boteva et al. (2012) genotyped 1,028 SLE cases, including 501 patients from the UK and 537 from Spain, and 1,179 controls for gene copy number (GCN) of total C4, C4A, C4B, and the 2-bp insertion SNP (C4AQ0; 120810.0001) resulting in a null allele. The loss-of-function SNP in C4A was not associated with SLE in either population. Boteva et al. (2012) used multiple logistic regression to determine the independence of C4 CNV from known SNP and HLA-DRB1 associations. Overall, the findings indicated that partial C4 deficiency states are not independent risk factors for SLE in UK and Spanish populations. Although complete homozygous deficiency of complement C4 is one of the strongest genetic risk factors for SLE, partial C4 deficiency states do not independently predispose to the disease.

Population Genetics

Ranford et al. (1987) found an extraordinarily high frequency of C4 deficiency in the Australian aboriginal population of Darwin: 29% as compared with 12% in aborigines in Alice Springs and 17% in Canberra blood donors. Partial C4B deficiency was also higher in Darwin aborigines than in the other populations.