Deficiency of the human complement regulatory protein factor H associated with low levels of component C9
D A Falcão1, E S Reis, D Paixão-Cavalcante
1Laboratório de Complemento, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Brazil.
Insights
Factor H (FH) deficiency in a child caused severe pneumonia. A genetic mutation (Arg127His) impaired FH secretion, impacting complement system proteins like C9.
Area of Science:
- Immunology
- Genetics
Background:
- Recurrent severe pneumonia can indicate underlying immune system dysfunction.
- The complement system, including factor H (FH), is crucial for immune defense and preventing self-damage.
Observation:
- A 4-year-old boy with Japanese-Brazilian heritage and consanguinity presented with severe recurrent pneumonia.
- He exhibited factor H deficiency, low C9, C3, and factor B levels.
- Family members showed varying degrees of FH deficiency and related protein level alterations.
Findings:
- The patient had a homozygous G453A substitution in the FH cDNA, resulting in an Arg(127)His amino acid change.
- Western blots confirmed the absence of FH and FHL-1 polypeptides in the patient.
- Fibroblast analysis indicated that the Arg(127) mutation might impede FH secretion.
Implications:
- This Arg(127)His mutation is linked to factor H deficiency and impaired FH secretion.
- The deficiency likely contributes to uncontrolled complement activation and C9 consumption, exacerbating pneumonia risk.
- Understanding FH secretion defects offers insights into complement-mediated diseases and potential therapeutic targets.
Abstract:
We identified a 4-year-old Brazilian boy from a family of Japanese descent and history of consanguinity, who suffered from severe recurrent pneumonia. He carries factor H (FH) deficiency associated with reduced levels of component C9 and low serum levels of C3 and factor B. His mother also presented low levels of these proteins and factor I, while his father and sister had only lower levels of FH. Western blot assays confirmed the complete absence of FH and FHL-1 polypeptides in this patient. Sequencing of the proband's FH cDNA revealed a homozygous G453A substitution, encoding an Arg(127)His change. His mother, father and sister are heterozygous for this substitution. Despite the absence of FH in the plasma, this protein was detected in the patient's fibroblasts, suggesting that Arg(127) may be important for FH secretion. Low concentrations of C9 were detected in the proband serum but no mutations in the patient's C9 gene or promoter have been identified, suggesting that this is a consequence of uncontrolled complement activation and high C9 consumption.
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