ELOC – von Hippel-Lindau disease

This summary describes the association between ELOC and von Hippel-Lindau disease. Patients fulfilling the clinical criteria for von Hippel-Lindau disease were traditionally found to harbor pathogenic variants in VHL; however, recent evidence has emerged demonstrating that variants in ELOC can also cause the disease. In one case report, a de novo variant in ELOC was identified in a proband with classic features of von Hippel-Lindau disease despite a negative genetic analysis for VHL variants (PMID:35323939).

The causal variant, reported as c.236A>G (p.Tyr79Cys), was identified through trio exome sequencing and confirmed using molecular studies on paired tumor and blood DNA samples. Although only a single proband was described, the de novo nature of this variant strengthens its pathogenicity in the clinical context (PMID:35323939).

The mutation c.236A>G (p.Tyr79Cys) affects a crucial residue in elongin C, a key component of the VCB-CR complex involved in oxygen sensing and hypoxia-inducible factor degradation. This disruption mimics the functional deficiency seen in pVHL, thereby providing a clear mechanistic link between the variant and the disease phenotype.

Supporting genetic evidence comes from the observation that the variant occurs de novo in the affected individual, leaving no room for familial segregation. The lack of additional affected relatives underscores the unique contribution of this single mutation to the observed phenotype (PMID:35323939).

In parallel, functional assessments have demonstrated that the p.Tyr79Cys substitution in elongin C disrupts its interaction with other components of the ubiquitin ligase complex. In vitro binding assays confirmed that the mutation severely impairs the formation and function of the VCB-CR complex, thereby recapitulating a cellular environment consistent with pVHL deficiency (PMID:10587522).

Collectively, these genetic and functional findings provide a coherent narrative that supports the role of ELOC variants as a novel cause of von Hippel-Lindau disease. Notably, the evidence suggests that genetic testing for ELOC variants is warranted in patients exhibiting VHL phenotypes but lacking identifiable VHL mutations.

Key take‑home: Incorporating ELOC analysis into the diagnostic workflow for suspected von Hippel-Lindau disease can enhance molecular diagnosis and guide therapeutic decisions, particularly for patients without detectable VHL gene alterations.

References

• Human Molecular Genetics • 2022 • Elongin C (ELOC/TCEB1)-associated von Hippel-Lindau disease PMID:35323939
• The Journal of Clinical Investigation • 1999 • Synthetic peptides define critical contacts between elongin C, elongin B, and the von Hippel-Lindau protein PMID:10587522

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