Novel compound heterozygous mutations in the C3 gene: hereditary C3 deficiency

Abstract

Key words complement component C3, compound heterozygous mutations, hereditary C3 deficiency, splice-site mutation.The complement system is a part of the innate immune system and plays an important role in host defense mechanisms. The pivotal complement factor C3 is the convergence point for the classical, lectin and alternative pathways of complement activation. C3 is synthesized predominantly by hepatocytes, although small amounts are also produced by activated monocytes, fibroblasts, endothelial cells, and smooth muscle cells. A single chain precursor (Pro-C3) of approximately 200 kDa is found intracellularly. This is then processed by proteolytic cleavage to yield the mature protein, which consists of two disulfide-linked subunits, a and b, with a molecular weight of 115 and 70 kDa, respectively. C3 is encoded by a 42-kb gene of 41 separate exons on chromosome 19. 1,2 Most of the patients with hereditary C3 deficiency are susceptible to recurrent bacterial infection. Some patients may develop immune-complex disorders such as glomerulonephritis and systemic lupus erythematosus. C3 deficiency has been described in 24 families including five Japanese. The detailed molecular basis of C3 deficiency has been investigated in only 12 families (14 individuals) including our reports, 3,4 representing a variety of ethnic and national origins. Almost all of the mutations were homozygous 5 except for a case of compound heterozygous we reported previously 4 and three cases (from two families) of suspected compound heterozygous after incomplete analysis. 6,7 Here we report the second confirmed case of hereditary C3 deficiency caused by novel compound heterozygous mutations. We detected mutations which consist of a nonsense and splice-site mutations, and further studied abnormal C3 transcripts derived from the splice mutation. Case reportThe patient was a 4-year-old Japanese boy who had suffered from two episodes of bacteremia caused by Streptococcus pneumoniae, pneumonia, acute otitis media, and gastroenterocolitis. His nonconsanguineous parents and his brother were all in good health. Laboratory examination of the patient revealed an extremely low level of serum C3 (0.3 mg/dL; normal range, 75-150 mg/dL) and CH 50 (4.7 U/mL; normal range, 35-45 U/ mL). Serum C3 levels of his mother, father, and brother were 40.0 mg/dL, 49.7 mg/dL, and 90.8 mg/dL, respectively. Serum C4 levels were all within normal range. Serum CH 50 levels of his mother, father, and brother were 31.7 U/mL, 42.8 U/mL, and 54.4 U/mL, respectively. Methods

Complement component C3 – The “Swiss Army Knife” of innate immunity and host defense

“…Meningitis and respiratory tract infections are the most prominent and include otitis, pneumonia, tonsillitis, and sinusitis, mainly caused by S. pneumoniae , H. influenzae , S. pyogenes , S. aureus , and N. meningitidis . In addition to infections, renal and lupus‐like diseases have been reported in 25% and 15% of C3‐deficient patients, respectively . To date, 40 cases of complete deficiency of C3 have been described worldwide, of which 21 have had the clinical diagnosis validated by molecular analysis .…”

“…In addition to infections, renal and lupus‐like diseases have been reported in 25% and 15% of C3‐deficient patients, respectively . To date, 40 cases of complete deficiency of C3 have been described worldwide, of which 21 have had the clinical diagnosis validated by molecular analysis . Notably, the onset of symptoms starts at about 2 years of age, and by the time of the case reports, 29% of the patients have had at least one sibling die at a very young age (less than 2 years old), indicating a critical role for C3 in childhood, when the adaptive immune system and antibody responses are not fully developed .…”

“…146,147 To date, 40 cases of complete deficiency of C3 have been described worldwide, of which 21 have had the clinical diagnosis validated by molecular analysis. [146][147][148][149] Notably, the onset of symptoms starts at about 2 years of age, and by the time of the case reports, 29% of the patients have had at least one sibling die at a very young age (less than 2 years old), indicating a critical role for C3 in childhood, when the adaptive immune system and antibody responses are not fully developed. 150 Interestingly, a recent report describing 41 French patients who were diagnosed with distinct complement deficiencies during adulthood did not include any C3-deficient patients.…”

Deficiencies of the Complement System

“…92,99À103 A complete listing is beyond the scope of this chapter. For example, mutations in the 5 0 donor splice site of intron 18 resulting in a premature stop codon have been identified, as has a mutation in intron 10.…”

“…35,92,93 Serum C3 is synthesized primarily in hepatocytes, although monocytes, fibroblasts, and endothelial and epithelial cells also produce C3. Activation of C3, through the classical pathway, lectin, or alternative pathway, generates two cleavage products, C3a and C3b.…”