CEBPE – Specific Granule Deficiency

Specific granule deficiency (SGD) is a rare autosomal recessive neutrophil disorder marked by absent or reduced neutrophil granules, neutropenia, and susceptibility to severe bacterial and fungal infections. Mutations in CCAAT/enhancer-binding protein epsilon (CEBPE) disrupt terminal neutrophil differentiation, leading to impaired antimicrobial function and atypical bilobed nuclei in affected neutrophils.

Autosomal recessive inheritance is supported by multiple families with homozygous or compound heterozygous CEBPE variants. In one pedigree, two brothers with recurrent cellulitis and one presenting with a brain abscess carried the homozygous nonsense variant c.403C>T (p.Arg135Ter) (PMID:32391290). A second family harbored a homozygous 11-base deletion c.655_665del (p.Lys220fs), resulting in profound neutropenia and severe infections in both siblings (PMID:35726044).

A multi-patient study identified two unrelated individuals heterozygous for the missense variant c.653T>C (p.Val218Ala), which prevented nuclear localization of C/EBPε and recapitulated SGD neutrophil phenotypes, including aberrant granule clustering and altered proteome composition (PMID:29651288). Across these reports, five distinct CEBPE variants (four loss-of-function and one missense) have been implicated in SGD.

Segregation analysis demonstrated variant segregation in two additional affected relatives, confirming cosegregation with disease. Functional assays—including dihydrorhodamine oxidative burst testing, flow cytometric granularity analysis, proteomic profiling, RT-PCR of granule proteins, luciferase reporter assays, and TLR-stimulated CD62L shedding—consistently revealed loss-of-function effects concordant with the human disease phenotype.

No studies to date dispute the role of CEBPE in SGD. Together, genetic segregation and robust functional evidence support a causal relationship between biallelic CEBPE loss-of-function or dominant-negative missense variants and specific granule deficiency.

Key Take-home: Biallelic CEBPE pathogenic variants cause autosomal recessive specific granule deficiency, guiding molecular diagnosis and informing lifelong antimicrobial prophylaxis and potential hematopoietic cell transplantation.

References

• Frontiers in Pediatrics • 2020 • Brain Abscess as Severe Presentation of Specific Granule Deficiency. PMID:32391290
• Journal of Clinical Immunology • 2022 • A Novel CEBPE Variant Causes Severe Infections and Profound Neutropenia. PMID:35726044
• Frontiers in Immunology • 2018 • CEBPE-Mutant Specific Granule Deficiency Correlates With Aberrant Granule Organization and Substantial Proteome Alterations in Neutrophils. PMID:29651288

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