Lizama-Muñoz Asier, Gutiérrez-Bautista Juan Francisco, Bernal Monica, López-Nevot Miguel Ángel
Department of Biochemistry, Molecular Biology and Immunology III, Faculty of Medicine, University of Granada, Granada, Spain.
Clinical analysis and Immunology Department, University Hospital Virgen de las Nieves, Granada, Spain.
Front Immunol. 2025 Jul 7;16:1605903. doi: 10.3389/fimmu.2025.1605903. eCollection 2025.
Patients with C5 mutations are more susceptibility to Gram-negative bacterial infections, particularly species.
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.
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.
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 infections. Siblings carrying only one variant had normal complement function. 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.
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.
携带C5基因突变的患者更易感染革兰氏阴性菌，尤其是奈瑟菌属。
描述一个携带两个C5基因变异体（包括一个新突变）的家系的表型和临床特征，并评估其功能和遗传意义。
我们分析了一个具有两个复合杂合C5变异体的家系的临床和遗传特征。对受影响和未受影响的家庭成员的临床特征进行评估，并将结果与遗传和功能检测相关联。
基因检测发现C5基因存在复合杂合变异体：c.713T>C（p.Ile238Thr）和c.1949G>T（p.Gly650Val）。位于外显子7的p.Ile238Thr变异体导致异亮氨酸被苏氨酸取代。位于外显子15的p.Gly650Val变异体使甘氨酸被缬氨酸取代。桑格测序证实这些变异体呈反式（位于不同等位基因上）。母亲与患者携带相同的两个变异体。两个兄弟姐妹分别携带一个变异体（分别为Gly650Val和Ile238Thr），一个兄弟姐妹为Ile238Thr变异体的纯合子。临床上，患者、母亲和纯合子兄弟姐妹的血清C5蛋白和CH50水平极低，这与侵袭性感染易感性增加相关。仅携带一个变异体的兄弟姐妹补体功能正常。结构分析和分子建模表明，这两个氨基酸取代（Ile238Thr和Gly650Val）可能破坏C5蛋白结构。Ile238Thr的变化用一个极性残基取代了一个疏水残基，破坏了疏水核心并在β折叠之间打开了一个环。Gly650Val的变化用一个较大的残基取代了一个较小的残基，导致空间位阻从而需要结构重排，包括一个环、α螺旋和β折叠的移位。
我们描述了一种新的C5变异体（Gly650Val）和一种先前报道的变异体（Ile238Thr），它们以独特的基因型组合（复合杂合和纯合）存在，与显著的C5缺乏和侵袭性奈瑟菌感染易感性增加相关。我们的研究结果强调了结合遗传、功能和结构数据来解释补体缺陷中变异体的重要性。
