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.

Severe infectious diseases of childhood as monogenic inborn errors of immunity

“…These findings unambiguously demonstrate that mutations in any one of several genes controlling a common component of a major arm of immunity can manifest as invasive diseases caused by a unique type of common pathogen. Moreover, a significant proportion of children with invasive meningococcal disease have been found to display one or other of these complement defects (42). However, these findings did not have as great an impact as the study of MSMD on the definition of candidate genetic architectures for infectious diseases, possibly because of the way in which they were obtained.…”

Complement factor 5 (C5) p.A252T mutation is prevalent in, but not restricted to, Sub-Saharan Africa: Implications for the susceptibility to meningococcal disease

“…The most relevant exception to this general observation is the p.A252T mutation, reported by Owen et al 21 .…”

“…The allele was present in both black Africans and Cape Coloured individuals, with allelic frequencies of 3 and 0.66%, respectively 21 . The populations in which the C5 p.A252T mutation has been detected, together with their heterozygosity frequencies, are summarized in Table 3.…”

“…To increase the representation from Africa, we collected 352 samples from Gabon (Central Africa) and 768 from North African countries (Morocco, Algeria, Tunisia and Libya). Other relevant data were provided by the 2090 African American individuals within the NHLBI Exome Sequencing Project (although their specific origin is not reported) and the 1500 individuals from South Africa described by Owen et al 21 . Based on the data from the present study and the above-mentioned available information, we estimated the heterozygosity frequency of the C5 p.A252T mutation in sub-Saharan Africa to be 0·5-2%.…”

“…A striking exception is the p.A252T mutation, reported recently to be responsible for C5 deficiency and found in approximately 7% of meningococcal disease cases in black Africans from the Western Cape (South Africa) 21 . This mutation has an allele frequency of 3% in the black African population and 0·66% in the Cape Coloured population of the Western Cape area 21 .…”