Abstract
Hereditary complete deficiency of complement component C1q is a rare genetic disorder that is associated with severe recurrent infections and a high prevalence of lupus-erythematosus-like symptoms. In the past, several single nucleotide polymorphisms have been identified in all three genes coding for the C1q A, B, and C chains. These point mutations which either lead to termination codons, frameshift, or amino acid exchanges were thought to be responsible for these defects as no other nonsense or missense mutations were found. As a result of the aberrations, either a nonfunctional C1q antigen is present or no C1q protein is detectable in the patients' sera. Screening 46 individuals from seven families with different forms of C1q deficiencies identified a homologous silent mutation at position Gly70 (GGG>GGA) of the C1q A gene of all 11 C1q-deficient patients. A high number of family members that were heterozygous for the coding mutations carried the silent mutation in the homozygous (18%) or heterozygous (36%) state. In addition to the Gly70 mutation in the A gene, another homozygous silent mutation (C gene at position Pro14, CCT>CCC) was detected in all C1q-deficient patients.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Berkel AI, Birben E, Öner C, Öner R, Loos M, Petry F (2000) Molecular, genetic and epidemiologic studies on selective complete C1q deficiency in Turkey. Immunobiology 201:347–355
Cartegni L, Chew SL, Krainer AR (2002) Listening to silence and understanding nonsense: exogenic mutations that effect splicing. Nat Rev Genet 3:285–298
Kirschfink M, Petry F, Khirwadkar K, Wigand R, Kaltwasser JP, Loos M (1993) Complete functional C1q deficiency associated with systemic lupus erythematosus (SLE). Clin Exp Immunol 94:267–272
McAdam RA, Goundis D, Reid KBM (1988) A homozygous point mutation results in a stop codon in the C1q B-chain of a C1q-deficient individual. Immunogenetics 27:259–264
Petry F (1998) Molecular basis of hereditary C1q deficiency. Immunobiology 199:284–294
Petry F, Loos M (1998) Bacteria and complement. In: Volanakis JE, Frank MM (eds) The human complement system in health and disease. Marcel Dekker Inc., New York, pp 375–392
Petry F, Le DT, Kirschfink M, Loos M (1995) Non-sense and missense mutations in the structural genes of complement component C1q A and C chains are linked with two different types of complete selective C1q deficiencies. J Immunol 155:4734–4738
Petry F, Berkel AI, Loos M (1997a) Multiple identification of a particular type of hereditary C1q deficiency in the Turkish population: review of the cases and additional genetic and functional analysis. Hum Genet 100:51–56
Petry F, Hauptmann G, Goetz J, Grosshans E, Loos M (1997b) Molecular basis of a new type of C1q-deficiency associated with a non-functional low molecular weight (LMW) C1q—parallels and differences to other known genetic C1q-defects. Immunopharmacology 38:189–202
Pfarr N, Prawitt D, Kirschfink M, Schroff C, Knuf M, Habermehl P, Mannhardt W, Zepp F, Fairbrother W, Loos M, Burge CB, Pohlenz J (2005) Linking C5 deficiency to an exonic splicing enhancer mutation. J Immunol 174:4172–4177
Racila DM, Sontheimer CJ, Sheffield A, Wisnieski JJ, Racila E, Sontheimer RD (2003) Homozygous single nucleotide polymorphism of the complement C1QA gene is associated with decreased levels of C1q in patients with subacute cutaneous lupus erythematosus. Lupus 12:124–132
Sellar GC, Blake DJ, Reid KBM (1991) Characterisation and organisation of the genes encoding the A, B and C chain of human C1q. The complete derived amino acid sequence of human C1q. Biochem J 274:481–490
Sellar GC, Cockburn D, Reid KBM (1992) Localization of the gene cluster encoding the A, B, and C chains of human C1q to 1p34.1–1p36.3. Immunogenetics 35:214–216
Slingsby JH, Norsworthy P, Pearce G, Vaishnaw AK, Issler H, Morley BJ, Walport MJ (1996) Homozygous hereditary C1q deficiency and systemic lupus erythematosus. A new family and the molecular basis of C1q deficiency in three families. Arthritis Rheum 39:663–670
Suwairi W, Bahabri S, Beving D, Wisnieski J, Warman M (1997) Dysfunctional and antigenetically abnormal C1q resulting from a point mutation in codon 6 of the C chain. Arthritis Rheum 40:S308
Topaloglu R, Bakkaloglu A, Slingsby JH, Mihatsch MJ, Pascual M, Norsworthy P, Morley BJ, Saatci U, Schifferli JA, Walport MJ (1996) Molecular basis of hereditary C1q deficiency associated with SLE and IgA nephropathy in a turkish family. Kidney Int 50:635–642
Walport MJ (2001) Complement. First of two parts. N Engl J Med 344:1058–1066
Walport MJ, Davies KA, Botto M (1998) C1q and systemic lupus erythematosus. Immunobiology 199:265–285
Walsh PS, Metzger DA, Higuchi R (1991) Chelex 100 as a medium for simple extraction of DNA for PCR-based typing from forensic material. Biotechniques 10:506–513
Acknowledgements
We thank Ms. Steffi Marx for excellent technical assistance. This work was supported in part by grant DFG-SFB490-C3.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Petry, F., Loos, M. Common silent mutations in all types of hereditary complement C1q deficiencies. Immunogenetics 57, 566–571 (2005). https://doi.org/10.1007/s00251-005-0023-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00251-005-0023-z