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Two of four siblings expressed the salt-losing form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) and had identical human lymphocyte antigen (HLA) and complement C4 (fourth component of complement) types (HLA-A3,C4,B35,C4A3,C4BQO,DR1/A2,C-,B18,C4A3, C4BQO,DR6). The father and one unaffected sibling were heterozygous carriers of CAH, as determined by a 30-min iv ACTH stimulation test and HLA typing. In addition, the iv ACTH stimulation test revealed that the mother and the other unaffected sibling also carried an allele for an attenuated form of CAH. Restriction endonuclease digests of genomic DNA obtained from members of this family and from normal unrelated subjects were hybridized with cDNA probes encoding human 21-hydroxylase and C4. With the 21-hydroxylase probe, Southern blots prepared from control DNA samples revealed two major restriction fragments in each of four restriction endonuclease digests; TaqI produced major bands at 3.7 and 3.2 kilobases (kb), KpnI at 4.0 and 2.9 kb, EcoRI at 18 and 13 kb, and BglII at 15 and 12.5 kb. Southern blots prepared from DNA of the two patients lacked the 3.7-kb TaqI and 2.9-kb KpnI fragments, but had increased hybridization intensity (relative to control DNA samples) in the 3.2-kb TaqI and 4.0-kb KpnI fragments. By contrast, blots with EcoRI or BglII had two large hybridization fragments not different from control DNA samples. These data indicate the presence of two different 21-hydroxylase genes. Additional mapping studies revealed that the two genes had the restriction pattern of the inactive 21-hydroxylase gene. When genomic DNA that had been isolated from all members of this family and from normal subjects was hybridized with the human C4 cDNA probe, the restriction fragment hybridization patterns for all four endonuclease digests were similar in the two groups. Hence, our results suggest that the 21-hydroxylase deficiency of our patients is due to conversion of the active 21-hydroxylase gene to the inactive gene. This gene conversion was associated with absence of functional C4B protein, without any detectable alterations in the restriction fragment pattern of the C4 genes.

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Polymorphism of three complement genes (C4A, C4B, and BF) located within the major histocompatibility complex was studied in 48 biopsy-proven IgA nephropathy patients and nineteen patients with Henoch-Schönlein purpura (HSP). Polymorphism was determined by immunoelectrophoretic techniques and functional activity using an overlay of sheep cells in agarose and C4 deficient sera. The subjects were divided into four large groups according to the presence or absence of a C4 null allele (a gene producing no identifiable gene product): group 1 (no null variants), group 2 (one C4A null variant), group 3 (one C4B null variant), and group 4 (two null variants at either the C4A or C4B locus, that is, homozygous null). Patients had a significantly increased frequency of group 4 phenotypes (homozygous null): (12 of 67 patients, 17.8%) as compared to controls (4 of 102 patients, 3.9%, P = 0.0031). Both IgA (P = 0.045) and HSP patients (P = 0.003) had a greater frequency of a C4 homozygous null phenotype. The serum C4 concentration was higher in patients than in controls (740 mg/ml and 576 micrograms/ml, respectively, P = less than 0.001) whether evaluated together or by C4 phenotypic group. The association between the presence of IgA nephropathy or HSP with a homozygous C4 null phenotype is of unknown significance but suggests a predisposition to development of HSP or IgA nephropathy for individuals with the C4 homozygous null phenotype.

A B S T R A C T The study of serum from a patient with C2 deficiency is described. The patient had an episode of pneumococcal meningitis at 5 mo of age with seizures and transient hemiparesis and apparent purpuric skin lesions. He was first admitted to the University of Minnesota Hospitals at 10 yr of age following the discovery of proteinuria accidentally by his mother. Since then he has been admitted repeatedly to this hospital with numerous clinical findings including arthralgia, recurrent abdominal pain, proteinuria, membranous nephropathy, malar butterfly rash, seizures, personality aberrations, and recurrent fever. In June 1971, the patient developed positive DNA and DNP antibodies and positive LE cells. When the C profile was studied before and after recognition of lupus, Clq, Cls, and C4 dropped. C3 levels were elevated as were C5, C6, and C7. C3 proactivator had been reduced in the patient even before he developed lupus. Also because of a traumatic renal biopsy leading to a perirenal hematoma, he required surgery and a blood transfusion. 1 h after blood transfusion, a C2 titer of 23 hemolytic units was detected. Almost immediately levels of C3, C5, C6, and C7 dropped. C8 and C9 remained elevated. The addition of C2 from normal blood permitted dramatic activation of C3.These findings support the view that the rare deficiency in production of C2 predisposes to serious susceptibility to infection, vascular and mesenchymal disease as well as to renal disease and a lupus syndrome.

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In a girl with recurrent haemolytic uraemic syndrome (HUS), persistently low serum levels of C3 were found. Analysis of complement phenotype revealed a hypomorphic variant of C3 Fast in the patient (C3fS) and a normal heterozygous pattern in both parents and the brother (C3FS). Other complement aberrations in the patient were: the presence of a null gene for C4A and C4B and low serum levels of factor H. The father also had partial factor H deficiency. It is hypothesized that the hypomorphic C3 variant may predispose to recurrent HUS. In the acquired forms the role of uraemia in alteration of C3F should be considered.