C1QC – C1q Deficiency

C1QC (HGNC:1245) encodes the collagen-like C chain of complement component C1q, initiating classical pathway activation. Autosomal recessive C1q deficiency (MONDO:0013343) results in absent serum C1q and impaired classical pathway function, manifesting as severe immunodeficiency and high penetrance of systemic lupus erythematosus (SLE).

Multiple homozygous and compound heterozygous loss-of-function (LoF) variants have been reported in at least eight unrelated probands across four families, including missense (c.17G>A (p.Ser6Asn)), nonsense (c.205C>T (p.Arg69Ter)), and frameshift (c.213del (p.Gln74fs)) changes (PMID:7594474; PMID:8630118).

Segregation analysis confirmed recessive inheritance, with heterozygous parents and affected offspring lacking C1q, although no additional affected relatives beyond index cases were described.

Functional studies demonstrate absent intact C1q assembly in patient sera and cell lysates, disruption of the Gly-X-Y collagen motif, and formation of low-molecular-weight C1q with impaired secretion, corroborated by splicing assays in non-coding region mutations (PMID:7594474; PMID:25454803).

Clinically, patients present in infancy with recurrent bacterial infections, cutaneous and renal involvement, and up to 20% develop neuropsychiatric SLE with seizures (HP:0001250) and basal ganglia vasculitis (PMID:28082982).

Integration of genetic and experimental data supports a strong autosomal recessive mechanism via complete loss of C1q activity. C1QC variant analysis is essential for early diagnosis and management of C1q deficiency.

Key Take-home: Autosomal recessive LoF variants in C1QC cause complete C1q deficiency with immunodeficiency and SLE, justifying genetic testing in early-onset lupus or recurrent infections.

References

• Journal of immunology (Baltimore, Md. : 1950) • 1995 • Non-sense and missense mutations in the structural genes of complement component C1q A and C chains are linked with two different types of complete selective C1q deficiencies. PMID:7594474
• Arthritis and rheumatism • 1996 • Homozygous hereditary C1q deficiency and systemic lupus erythematosus. A new family and the molecular basis of C1q deficiency in three families. PMID:8630118
• Immunobiology • 2015 • Identification of a novel non-coding mutation in C1qB in a Dutch child with C1q deficiency associated with recurrent infections. PMID:25454803
• Frontiers in immunology • 2016 • C1q Deficiency and Neuropsychiatric Systemic Lupus Erythematosus. PMID:28082982

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