Christina Gavino1, Nancy Hamel2, Ji Bin Zeng1, Catherine Legault3, Marie-Christine Guiot4, Jeffrey Chankowsky5, Duncan Lejtenyi6, Martine Lemire7, Isabelle Alarie8, Simon Dufresne9, Jean-Nicolas Boursiquot10, Fiona McIntosh11, Mélanie Langelier1, Marcel A Behr12, Donald C Sheppard13, William D Foulkes2, Donald C Vinh14. 1. Infectious Disease Susceptibility Program, McGill University Health Centre (MUHC) and Research Institute-MUHC (RI-MUHC), Montreal, Quebec, Canada. 2. Department of Medical Genetics, RI-MUHC, Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada. 3. Department of Neurology, MUHC, Montreal, Quebec, Canada. 4. Department of Pathology, MUHC, Montreal, Quebec, Canada. 5. Department of Radiology, MUHC, Montreal, Quebec, Canada. 6. Department of Pediatrics, MUHC, Montreal, Quebec, Canada. 7. Division of Allergy & Clinical Immunology, MUHC, Montreal, Quebec, Canada. 8. Department of Microbiology and Infectious Diseases, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada. 9. Department of Microbiology and Infectious Diseases, Hôpital Maisonneuve-Rosemont, Montreal, Quebec, Canada. 10. Department of Clinical Immunology and Allergy, Centre Hospitalier Universitaire de Québec, Quebec City, Quebec, Canada. 11. McGill International TB Centre, RI-MUHC, Montreal, Quebec, Canada. 12. McGill International TB Centre, RI-MUHC, Montreal, Quebec, Canada; Departments of Microbiology and Immunology and Medicine, McGill University, Montreal, Quebec, Canada. 13. Departments of Microbiology and Immunology and Medicine, McGill University, Montreal, Quebec, Canada. 14. Infectious Disease Susceptibility Program, McGill University Health Centre (MUHC) and Research Institute-MUHC (RI-MUHC), Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada. Electronic address: donald.vinh@mcgill.ca.
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.
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.
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