title: A complement C5 gene mutation, c.754G>A:p.A252T, is common in the Western Cape, South Africa and found to be homozygous in seven percent of Black African meningococcal disease cases.
abstract: Patients with genetically determined deficiency of complement component 5 are usually diagnosed because of recurrent invasive Neisseria meningitidis infections. Approximately 40 individual cases have been diagnosed worldwide. Nevertheless, reports of the responsible genetic defects have been sporadic, and we know of no previous reports of C5 deficiency being associated with a number of independent meningococcal disease cases in particular communities. Here we describe C5 deficiency in seven unrelated Western Cape, South African families. Three different C5 mutations c.55C>T:p.Q19X, c.754G>A:p.A252T and c.4426C>T:p.R1476X were diagnosed in index cases from two families who had both presented with recurrent meningococcal disease. p.Q19X and p.R1476X have already been described in North American Black families and more recently p.Q19X in a Saudi family. However, p.A252T was only reported in SNP databases and was not associated with disease until the present study was undertaken in the Western Cape, South Africa. We tested for p.A252T in 140 patients presenting with meningococcal disease in the Cape Town area, and found seven individuals in five families who were homozygous for the mutation p.A252T. Very low serum C5 protein levels (0.1-4%) and correspondingly low in vitro functional activity were found in all homozygous individuals. Allele frequencies of p.A252T in the Black African and Cape Coloured communities were 3% and 0.66% and estimated homozygosities are 1/1100 and 1/22,500 respectively. In 2012 we reported association between p.A252T and meningococcal disease. Molecular modelling of p.A252T has indicated an area of molecular stress in the C5 molecule which may provide a mechanism for the very low level in the circulation. This report includes seven affected families indicating that C5D is not rare in South Africa.
authors.affiliation: Department of Clinical Sciences, University of Cape Town, South Africa.
authors.forename: E Patricia
authors.initials: EP
authors.lastname: Owen
authors.affiliation: Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Würzner
authors.affiliation: Department of Clinical Sciences, University of Cape Town, South Africa.
authors.forename: Felicity
authors.initials: F
authors.lastname: Leisegang
authors.affiliation: Institute of Infection and Immunity, Cardiff University, Cardiff, UK.
authors.forename: Pierre
authors.initials: P
authors.lastname: Rizkallah
authors.affiliation: Department of Clinical Sciences, University of Cape Town, South Africa.
authors.forename: Andrew
authors.initials: A
authors.lastname: Whitelaw
authors.affiliation: Department of Clinical Sciences, University of Cape Town, South Africa.
authors.forename: John
authors.initials: J
authors.lastname: Simpson
authors.affiliation: Institute of Infection and Immunity, Cardiff University, Cardiff, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Thomas
authors.affiliation: Institute of Infection and Immunity, Cardiff University, Cardiff, UK.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Harris
authors.affiliation: Institute of Infection and Immunity, Cardiff University, Cardiff, UK.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Giles
authors.affiliation: Department of Immunology, Oslo University Hospital, National Hospital, University of Oslo, 0424 Oslo, Norway.
authors.forename: Bernt C
authors.initials: BC
authors.lastname: Hellerud
authors.affiliation: Department of Immunology, Oslo University Hospital, National Hospital, University of Oslo, 0424 Oslo, Norway.
authors.forename: Tom E
authors.initials: TE
authors.lastname: Mollnes
authors.affiliation: Institute of Infection and Immunity, Cardiff University, Cardiff, UK.
authors.forename: B Paul
authors.initials: BP
authors.lastname: Morgan
authors.affiliation: Allergy Diagnostic and Clinical Research Unit, Department of Medicine, Lung Institute, University of Cape Town, South Africa.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Potter
authors.affiliation: Department of Clinical Sciences, University of Cape Town, South Africa; Institute of Infection and Immunity, Cardiff University, Cardiff, UK; Allergy Diagnostic and Clinical Research Unit, Department of Medicine, Lung Institute, University of Cape Town, South Africa. Electronic address: orrena@cardiff.ac.uk.
authors.forename: Ann
authors.initials: A
authors.lastname: Orren
mesh_terms: D000293:Adolescent; D000328:Adult; D044383:Black People / Q000235:genetics*; D003167:Complement Activation / Q000276:immunology; D003182:Complement C5 / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D000081208:Hereditary Complement Deficiency Diseases; D006720:Homozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics; D007231:Infant, Newborn; D008297:Male; D008585:Meningitis, Meningococcal / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D009154:Mutation / Q000235:genetics*; D059645:Mutation Rate; D010375:Pedigree; D013019:South Africa; D055815:Young Adult
chemical_list: D003182:Complement C5
keywords: Black African; Complement C5 deficiency; Meningococcal disease