PRKCD – Common Variable Immunodeficiency

Protein kinase C delta (PKCδ), encoded by PRKCD (HGNC:9399), is a novel protein kinase critical for B-cell tolerance and apoptosis. Common variable immunodeficiency (CVID) (MONDO:0015517) manifests with hypogammaglobulinemia, recurrent infections, and impaired vaccine responses, and <20% of CVID cases have a defined monogenic etiology. Recent genomic studies and case reports implicate autosomal recessive PRKCD loss-of-function variants in a CVID-like B-cell deficiency.

Autosomal recessive inheritance is supported by biallelic PRKCD variants in affected individuals. One consanguineous patient harbored NM_006254.4(PRKCD):c.1182del (p.Met395fs) (PMID:23319571), and an independent WES cohort identified a second unrelated CVID proband with PRKCD LoF (PMID:29867916), totaling 2 probands. No additional segregating relatives have been reported.

Genetic spectrum is characterized by frameshift and splice-site mutations leading to absent or truncated PKCδ protein; the canonical variant c.1182del (p.Met395fs) abolishes catalytic activity. These LoF variants reduce substrate phosphorylation and impair class-switch recombination, consistent with loss-of-function mechanism.

Functional assays in patient-derived B cells demonstrate absent PKCδ expression, decreased MARCKS phosphorylation, resistance to B-cell receptor-mediated apoptosis, and increased IL-6 transcription (PMID:23319571). Rescue of apoptosis by PRKCD reconstitution in patient cell lines further confirms causality (PMID:23430113). Murine PKCδ deficiency recapitulates the B-cell hyperproliferation and hypogammaglobulinemia seen in human CVID.

Collectively, limited genetic evidence from 2 unrelated probands combined with strong functional concordance establishes a Limited ClinGen gene–disease association. Additional case series may strengthen the evidence, but current data support PRKCD testing in early-onset CVID patients.

Key Take-home: AR PRKCD LoF variants underlie a CVID-like syndrome by impairing B-cell apoptosis and antibody production, and should be included in diagnostic gene panels for CVID.

References

• Frontiers in immunology • 2018 • Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond. PMID:29867916
• Blood • 2013 • B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C δ PMID:23319571
• Blood • 2013 • Loss-of-function of the protein kinase C ζ (PKCζ) causes a B-cell lymphoproliferative syndrome in human PMID:23430113

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