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

Abstract

Complement C5 deficiency (C5D) is a rare primary immunodeficiency associated with recurrent infections, particularly meningitis, by Neisseria species. To date, studies to elucidate the molecular basis of hereditary C5D have included fewer than 40 families, and most C5 mutations (13 of 17) have been found in single families. However, the recently described C5 p.A252T mutation is reported to be associated with approximately 7% of meningococcal disease cases in South Africa. This finding raises the question of whether the mutation may be prevalent in other parts of Africa or other continental regions. The aim of this study was to investigate the prevalence of C5 p.A252T in Africa and other regions and discuss the implications for prophylaxis against meningococcal disease. In total, 2710 samples from healthy donors within various populations worldwide were analysed by quantitative polymerase chain reaction (qPCR) assay to detect the C5 p.A252T mutation. Eleven samples were found to be heterozygous for p.A252T, and nine of these samples were from sub-Saharan African populations (allele frequency 0·94%). Interestingly, two other heterozygous samples were from individuals in populations outside Africa (Israel and Pakistan). These findings, together with data from genomic variation databases, indicate a 0·5-2% prevalence of the C5 p.A252T mutation in heterozygosity in sub-Saharan Africa. Therefore, this mutation may have a relevant role in meningococcal disease susceptibility in this geographical area.

Clinical and Genetic Spectrum of a Large Cohort With Total and Sub-total Complement Deficiencies

“…C7 deficiency caused by the pathogenic variant p.Gly379Arg is reported in 1% of the Israeli Moroccan Jewish population (39). C6 deficiency has a high prevalence in western Cape South Africans and in African Americans (40, 41) and the C5 variant p.Ala252Thr leading to subtotal C5 deficiency is prevalent in sub–Saharan Africa (22). In our study, we identified 15 recurrent deleterious variants in genes coding for the lytic complex.…”

“…If the MBL deficiency is common, CD are generally rare, with an estimated prevalence of 5% of all primary immunodeficiencies (7). Published data of CD are limited to single case reports (14–19), small case series (20, 21), and few multicenter studies (9, 22, 23), evaluating clinical manifestations. Here, we report the immunological, genetic, and clinical features of the largest worldwide cohort ever described of 212 patients with total or sub-total complement deficiencies.…”

Komplemento Sistemos Komponentų Įtaka N. Meningitidis Sukeliamai Infekcijai

“…atvejų [21]. Mažas C8 komponento kiekis dažniausiai siejamas su C8B taškinės mutacijos variantu c.1282C>T (p.Arg428*) [11,22].…”

“…Toliau pateikiamos pagrindinės atskirų komplemento komponentų genetinės mutacijos bei jų paplitimas tarp meningokokine infekcija sirgusių pacientų (1 lentelė). [11]. Didelis šios mutacijos paplitimas šioje geografinėje teritorijoje yra viena iš joje registruojamo ypač didelio sergamumo invazine meningokokine infekcija, vadinamojo "meningokokinio diržo", priežasčių ir siejamas su maždaug 7 proc.…”

“…ligos atvejų [10]. Ši mutacija kiek rečiau registruojama ir kitose populiacijose [11]. Kita svarbi su C5 trūkumu siejama mutacija yra rėmelio tipo delecija 960_962delCAA [9].…”