C7 Deficiency and Meningococcal Infection Susceptibility in Two Spanish Families

Abstract

In this work, we report the genetic basis of C7 deficiency in two different Spanish families. In family 1, by using exon‐specific polymerase chain reaction and sequencing, a recently described mutation was found in homozygosity in the patient; a single base change in exon 15 (C2107T) leading to a stop codon that causes truncation of the C‐terminal portion of C7 (Q681X). Patient’s father, mother and sister were heterozygous for this mutation. Interestingly, patient’s parents were not related. In family 2, a new single base mutation in exon 2 (G90A), leading to a stop codon that causes the premature truncation of C7 (W8X), was found in the patient, mother and sister 1. Additionally, patient 2, her father and sisters, displayed a missense mutation in exon 9 (G1135C) resulting in a change of aminoacid (G357R). Although sister 1 bore the same mutations in the C7 gene that patient 2, she remains asymptomatic. Because both mutations were found in the patient and her sister, we analyse other defence mechanisms such as FcγR polymorphisms as well as mannose‐binding lectin alleles (MBL2 gene) and MBL levels. Results showed that both siblings bore identical combinations of FcγR allotypes and different MBL2 alleles, exhibiting patient 2 a MBL‐insufficient genotype. Normal MBL levels were found in patient 1 and in two previously studied C7‐deficient siblings, suggesting the involvement of other mechanisms of immunity distinct of FcγR variants and the MBL pathway, for the absence of meningococcal recurrent infections in certain C7‐deficient individuals.

Functional genetic variants in complement component 7 confer susceptibility to gastric cancer

“…As an essential part of the membrane attack complex (MAC), C7 participated in various microbial defense responses and immune injury responses. The lack of C7 may affect the function of MAC and further increase the susceptibility to infection ( Barroso et al, 2010 ; Sarma & Ward, 2011 ). Tumor infection promoted cancer aggression, prevented inflammation, reduces metastasis and improved anti-tumor treatment ( Maller et al, 2021 ).…”

The novel p.Gly306Asp perforin mutation causes Familial Hemophagocytic Lymphohistiocytosis type 2 (FHL-2) probably due to a critical role of Gly306 in the pore-forming perforin domain.

“…Protein destabilization results in misfolding and premature degradation, and correlates positively with the degree of protein dysfunction and clinical severity (Pey et al 2007;Tokuriki et al 2008;Tokuriki and Tawfik 2009;McKeone et al 2014). Interestingly, the Arginine mutation of Gly357 in the complement factor C7-a glycine corresponding to Gly305 in perforin, is one of the most frequent mutations associated with C7 deficiency, and was linked to serious misfolding and defective secretion (Fernie et al 1997;Barroso et al 2004;Rameix-Welti et al 2007;Barroso et al 2010).…”

C7 genotype of the donor may predict early bacterial infection after liver transplantation

“…C7 is one of the five terminal complement proteins (C5, C6, C7, C8, and C9) that interact sequentially to form a large protein-protein complex, called the MAC, following activation of the complement cascade via the classical, alternative, or lectin pathways. The MAC lyses foreign pathogens directly 14 ; hence, C7 deficiency can affect the formation of the MAC, resulting in increased susceptibility to infection 19 20 21 . Thus, this mechanism may account for the increased susceptibility of recipients of livers with the rs6876739 CC genotype to infection after LT.…”