The molecular basis of hereditary complement factor I deficiency

Area of Science:

• Immunogenetics
• Molecular Medicine
• Biochemistry

Background:

• Hereditary complement factor I deficiency is a rare genetic disorder affecting the immune system.
• Complement factor I plays a crucial role in regulating the complement cascade, preventing excessive immune responses.
• Understanding the molecular basis of this deficiency is key to diagnosing and potentially treating associated infections.

Purpose of the Study:

• To elucidate the molecular basis of hereditary complement factor I deficiency in two distinct pedigrees.
• To identify specific genetic mutations responsible for complement factor I deficiency.
• To correlate genotype with clinical phenotype in affected individuals.

Main Methods:

• Analysis of complement factor I mRNA using reverse transcription and polymerase chain reaction (RT-PCR).
• DNA sequencing to identify specific nucleotide substitutions and splice site mutations.
• Genotyping of affected individuals within two pedigrees.

Main Results:

• Identified a transversion mutation (adenine to thymine at nucleotide 1282) in both siblings of the first pedigree, leading to a histidine-400 to leucine substitution.
• The proband of the second pedigree was a compound heterozygote, carrying the same transversion mutation on one allele.
• The second allele in the second pedigree exhibited a donor splice site mutation, causing the deletion of exon 5 (encoding a low-density lipoprotein receptor domain) from the transcript.

Conclusions:

• Specific mutations in the complement factor I gene underlie hereditary deficiency.
• The identified mutations, including a missense mutation and a splice site mutation, disrupt factor I function.
• Genotype-phenotype correlations highlight the importance of complement factor I in preventing pyogenic infections.