C1q deficiency in an Inuit family: identification of a new class of C1q disease-causing mutations

Area of Science:

• Immunology
• Genetics
• Rare Diseases

Background:

• C1q deficiency is a rare genetic disorder.
• It is associated with systemic lupus erythematosus (SLE)-like symptoms and recurrent infections.
• The classical complement pathway is impaired in C1q deficiency.

Purpose of the Study:

• To investigate the molecular basis of C1q deficiency in three Inuit sisters.
• To identify the genetic cause of impaired classical complement pathway function.

Main Methods:

• Patients' sera were analyzed for complement pathway function and C1q levels.
• Genetic sequencing of C1q genes was performed.
• Family members and healthy controls were genotyped.

Main Results:

• The patients exhibited no function in the classical complement pathway, while lectin and alternative pathways were intact.
• No C1q or low molecular weight C1q was detected in patient sera.
• A novel missense mutation (Gly-Arg) in codon 217 of the C1q B chain was identified.
• All affected sisters were homozygous for the mutation, with heterozygous parents and no affected controls.

Conclusions:

• A novel missense mutation in the C1q B chain is the cause of C1q deficiency in this family.
• This finding represents a third class of molecular mechanisms for C1q deficiency.
• Missense mutations can lead to a complete lack of detectable C1q antigen in serum.