Impaired RASGRF1/ERK-mediated GM-CSF response characterizes CARD9 deficiency in French-Canadians.

Abstract

BACKGROUND:

Caspase recruitment domain-containing protein 9 (CARD9) deficiency is an autosomal recessive primary immunodeficiency conferring human susceptibility to invasive fungal disease, including spontaneous central nervous system candidiasis (sCNSc). However, clinical characterization of sCNSc is variable, hindering its recognition. Furthermore, an in-depth understanding of the bases for this susceptibility has remained elusive.

OBJECTIVES:

We sought to comprehensively characterize sCNSc and to dissect the mechanisms by which a hypomorphic CARD9 mutation causes susceptibility to Candida species.

METHODS:

We describe the clinical and radiologic findings of sCNSc caused by CARD9 deficiency in a French-Canadian cohort. We performed genetic, cellular, and molecular analyses to further decipher its pathophysiology.

RESULTS:

In our French-Canadian series (n = 4) sCNSc had onset in adulthood (median, 38 years) and was often misinterpreted radiologically as brain malignancies; 1 patient had additional novel features (eg, endophthalmitis and osteomyelitis). CARD9 deficiency resulted from a hypomorphic p.Y91H mutation and allelic imbalance established in this population through founder effects. We demonstrate a consistent cellular phenotype of impaired GM-CSF responses. The ability of CARD9 to complex with B-cell CLL/lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is intact in our series, arguing against its involvement in susceptibility to fungi. Instead, we show that the p.Y91H mutation impairs the ability of CARD9 to complex with Ras protein-specific guanine nucleotide-releasing factor 1 (RASGRF1), leading to impaired activation of nuclear factor κB and extracellular signal-regulated kinase (ERK) in monocytes and subsequent GM-CSF responses. Successful treatment of a second patient with adjunctive GM-CSF bolsters the clinical relevance of these findings.

CONCLUSIONS:

Hypomorphic CARD9 deficiency caused by p.Y91H results in adult-onset disease with variable penetrance and expressivity. Our findings establish the CARD9/RASGRF1/ERK/GM-CSF axis as critical to the pathophysiology of sCNSc.

• Authors: Christina Gavino, Nancy Hamel, Ji Bin Zeng, Catherine Legault, Marie-Christine Guiot, Jeffrey Chankowsky, Duncan Lejtenyi, Martine Lemire, Isabelle Alarie, Simon Dufresne, Jean-Nicolas Boursiquot, Fiona McIntosh, Mélanie Langelier, Marcel A Behr, Donald C Sheppard, William D Foulkes, Donald C Vinh
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 137 Issue 4 Pg. 1178-1188.e7 (Apr 2016) ISSN: 1097-6825 [Electronic] United States
• PMID: 26521038 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers
• CARD Signaling Adaptor Proteins
• CARD9 protein, human
• Genetic Markers
• RASGRF1 protein, human
• ras-GRF1
• Granulocyte-Macrophage Colony-Stimulating Factor
• Extracellular Signal-Regulated MAP Kinases

Topics

• Adult
• Biomarkers (metabolism)
• CARD Signaling Adaptor Proteins (deficiency, genetics)
• Candidiasis, Invasive (diagnosis, genetics, immunology)
• Central Nervous System Fungal Infections (diagnosis, genetics, immunology)
• Cohort Studies
• Extracellular Signal-Regulated MAP Kinases (immunology, metabolism)
• Female
• Genetic Markers
• Granulocyte-Macrophage Colony-Stimulating Factor (immunology, metabolism)
• Humans
• Immunologic Deficiency Syndromes (diagnosis, genetics, microbiology)
• Male
• Point Mutation
• Quebec
• Real-Time Polymerase Chain Reaction
• ras-GRF1 (immunology, metabolism)