@misc{10481/106144,
year = {2025},
month = {7},
url = {https://hdl.handle.net/10481/106144},
abstract = {Background: Patients with C5 mutations are more susceptibility to Gramnegative bacterial infections, particularly Neisseria species.
Objective: To describe the phenotype and clinical features of a family carrying
two C5 gene variants, including one novel mutation, and to assess their
functional and genetic significance.
Methods: We analyzed the clinical and genetic characteristics of a family with
two compounds heterozygous C5 variants. Clinical features were assessed
across affected and unaffected family members, and results were correlated
with genetic and functional assays.
Results: Genetic testing revealed compound heterozygous variants in the C5
gene: c.713T>C (p.Ile238Thr) and c.1949G>T (p.Gly650Val). The p.Ile238Thr
variant, located in exon 7, results in a substitution of isoleucine with threonine.
The p.Gly650Val variant, located in exon 15, replaces glycine with valine. Sanger
sequencing confirmed the variants were in trans (on separate alleles). The mother
carried the same two variants as the patient. Two siblings carried one variant each
(Gly650Val and Ile238Thr, respectively), and one sibling was homozygous for the
Ile238Thr variant.Clinically, the patient, the mother, and the homozygous sibling
had very low serum C5 protein and CH50 levels, correlating with increased
susceptibility to Neisseria infections. Siblings carrying only one variant had
normal complement function. In silico analysis and molecular modeling
indicate that both amino acid substitutions (Ile238Thr and Gly650Val) may
disrupt C5 protein structure. The Ile238Thr change introduces a polar residue
in place of a hydrophobic one, disrupting the hydrophobic core and opening a
loop between beta-sheets. The Gly650Val change substitutes a small residue
with a larger one, causing steric hindrance that necessitates structural
rearrangements, including shifts in a loop, alpha-helix, and beta-sheet. Conclusion: We describe a novel C5 variant (Gly650Val) a previously reported
variant (Ile238Thr) in unique genotypic combinations (compound heterozygous
and homozygous) associated with marked C5 deficiency and increased
susceptibility to invasive Neisseria infections. Our findings underscore the
importance of combining genetic, functional, and structural data for variant
interpretation in complement deficiencies.},
organization = {Instituto de Salud Carlos III (CM23/00098)},
organization = {Palex Medical S.A.},
publisher = {Frontiers Research Foundation},
keywords = {Complement deficiency},
keywords = {C5 deficiency},
keywords = {C5 mutation},
keywords = {Novel mutation},
keywords = {Phenotype and genotype},
title = {Description and phenotype of a novel C5 gene mutation and a novel combination: family report and literature review},
doi = {10.3389/fimmu.2025.1605903},
author = {Lizama-Muñoz, Asier and Gutiérrez-Bautista, Juan Francisco and Bernal, Monica and López Nevot, Miguel Ángel},
}