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Published on: July 14, 2016
Molecular defects leading to human complement component C6 deficiency in an African-American family
Z B Zhu1, K Totemchokchyakarn, T P Atkinson
1Department of Medicine, University of Alabama at Birmingham, 35294-0006, USA.
Insights
Complement component C6 deficiency (C6D) was diagnosed in a young male with meningococcal meningitis. Genetic analysis revealed compound heterozygous mutations in the C6 gene, explaining the deficiency and its inheritance pattern.
Area of Science:
- Immunology
- Human Genetics
Background:
- Complement component C6 deficiency (C6D) is a rare genetic disorder affecting the complement system, crucial for immune defense.
- Neisserial infections, such as meningococcal meningitis, are more prevalent in individuals with deficiencies in the terminal complement pathway.
Observation:
- A 16-year-old African-American male with meningococcal meningitis was diagnosed with C6D.
- His father and two brothers also had C6D, though without a history of neisserial infections.
Findings:
- Genetic analysis identified compound heterozygous mutations in the C6 gene: a novel 1195delC mutation in exon 7 and a previously described 1936delG mutation in exon 12.
- Both mutations lead to premature termination codons, resulting in C6 null alleles.
- Family segregation analysis confirmed inheritance of the 1195delC mutation from the mother and the 1936delG mutation from the father.
Implications:
- This study identifies novel genetic mutations causing C6 deficiency and elucidates their inheritance pattern within a family.
- Understanding the genetic basis of C6D is crucial for diagnosing and managing complement deficiencies and associated infections.
- The findings highlight that C6D may not always manifest with severe neisserial infections, suggesting other contributing factors to disease susceptibility.
Abstract:
Complement component C6 deficiency (C6D) was diagnosed in a 16-year-old African-American male with meningococcal meningitis. The patient's father and two brothers also had C6D, but gave no history of meningitis or other neisserial infection. By using exon-specific polymerase chain reaction (PCR)/single-strand conformation polymorphism as a screening step and nucleotide sequencing of target exons, we determined that the proband was a compound heterozygote for two C6 gene mutations. The first, 1195delC located in exon 7, is a novel mutation, while the second, 1936delG in exon 12, has been described before to cause C6D in an unrelated African-American individual. Both mutations result in premature termination codons and C6 null alleles. Allele-specific PCR indicated that the proband's two brothers also inherited the 1195delC mutation from their heterozygous mother and the 1936delG mutation from their homozygous father.
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