CARD6 and Primary Myelofibrosis

The CARD6 gene (HGNC:16394) has been implicated in primary myelofibrosis (MONDO_0009692) through the identification of a somatic nonsense mutation in a patient undergoing comprehensive whole‐genome sequencing (PMID:23872309). This variant, although reported only in a single index case, highlights a potential role of CARD6 in modulating NF‑κB activation, a pathway that is known to be involved in hematologic malignancies. The initial report provides a mechanistic hypothesis wherein the loss‐of‐function of CARD6 may contribute to disease pathogenesis via deregulated cell signaling. Despite the biological plausibility, the supporting genetic evidence is based on one proband with no additional family or recurrent case data.

In a subsequent multi-patient study involving 178 individuals with myeloproliferative neoplasms, re-sequencing of CARD6 and other candidate genes failed to identify recurrent somatic mutations in CARD6 (PMID:23872309). This finding suggests that although the initial observation is intriguing, the overall frequency of CARD6 alterations in primary myelofibrosis is very low. Consequently, the genetic evidence for a definitive association is limited, and the lack of segregation data or additional independent replication further tempers the strength of the association.

Complementary functional evidence comes from a separate study in a spinal cord injury murine model, where CARD6 was shown to modulate NF‑κB signaling, apoptosis, and inflammatory responses (PMID:31841440). In this context, CARD6 knockout significantly accelerated tissue injury, while overexpression provided protection, supporting its role in key regulatory pathways. Although the functional experiments were conducted in a model of spinal cord injury, they lend credence to the biological relevance of CARD6 in regulating processes that may also be important in hematologic malignancies such as primary myelofibrosis.

The integration of both genetic and functional studies presents a coherent narrative in which a single somatic nonsense mutation in CARD6 may have pathogenic significance in primary myelofibrosis through its impact on NF‑κB mediated pathways. However, the failure to detect recurrent mutations in larger patient cohorts underscores that the observed genetic evidence is currently limited. Further studies, including additional functional assessments in hematopoietic contexts and broader cohort analyses, are necessary to establish a more definitive link.

Overall, the available evidence supports a limited but biologically plausible role for CARD6 in primary myelofibrosis. The genetic evidence is primarily derived from a single case report, and while functional studies solidify the gene’s role in key cellular pathways, the scarcity of recurring variants limits its clinical impact at this time. Clinicians and researchers should view CARD6 as a candidate gene whose potential pathogenicity warrants additional investigation in the context of myeloproliferative neoplasms.

Key Take‑home Sentence: Despite limited genetic replication, the combination of a reported somatic nonsense mutation and supportive functional data on NF‑κB regulation underscores the potential clinical utility of CARD6 as a candidate in primary myelofibrosis, meriting further research.

References

• Haematologica • 2013 • Comprehensive whole‐genome sequencing of an early‐stage primary myelofibrosis patient defines low mutational burden and non‐recurrent candidate genes PMID:23872309
• Aging • 2019 • Targeting CARD6 attenuates spinal cord injury (SCI) in mice through inhibiting apoptosis, inflammation and oxidative stress associated ROS production PMID:31841440

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