title: 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.
  
  
  OBJECTIVE
  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.affiliation: Infectious Disease Susceptibility Program, McGill University Health Centre (MUHC) and Research Institute-MUHC (RI-MUHC), Montreal, Quebec, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Gavino
authors.affiliation: Department of Medical Genetics, RI-MUHC, Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Nancy
authors.initials: N
authors.lastname: Hamel
authors.affiliation: Infectious Disease Susceptibility Program, McGill University Health Centre (MUHC) and Research Institute-MUHC (RI-MUHC), Montreal, Quebec, Canada.
authors.forename: Ji Bin
authors.initials: JB
authors.lastname: Zeng
authors.affiliation: Department of Neurology, MUHC, Montreal, Quebec, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Legault
authors.affiliation: Department of Pathology, MUHC, Montreal, Quebec, Canada.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Guiot
authors.affiliation: Department of Radiology, MUHC, Montreal, Quebec, Canada.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Chankowsky
authors.affiliation: Department of Pediatrics, MUHC, Montreal, Quebec, Canada.
authors.forename: Duncan
authors.initials: D
authors.lastname: Lejtenyi
authors.affiliation: Division of Allergy & Clinical Immunology, MUHC, Montreal, Quebec, Canada.
authors.forename: Martine
authors.initials: M
authors.lastname: Lemire
authors.affiliation: Department of Microbiology and Infectious Diseases, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Alarie
authors.affiliation: Department of Microbiology and Infectious Diseases, Hôpital Maisonneuve-Rosemont, Montreal, Quebec, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Dufresne
authors.affiliation: Department of Clinical Immunology and Allergy, Centre Hospitalier Universitaire de Québec, Quebec City, Quebec, Canada.
authors.forename: Jean-Nicolas
authors.initials: JN
authors.lastname: Boursiquot
authors.affiliation: McGill International TB Centre, RI-MUHC, Montreal, Quebec, Canada.
authors.forename: Fiona
authors.initials: F
authors.lastname: McIntosh
authors.affiliation: Infectious Disease Susceptibility Program, McGill University Health Centre (MUHC) and Research Institute-MUHC (RI-MUHC), Montreal, Quebec, Canada.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Langelier
authors.affiliation: McGill International TB Centre, RI-MUHC, Montreal, Quebec, Canada; Departments of Microbiology and Immunology and Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Marcel A
authors.initials: MA
authors.lastname: Behr
authors.affiliation: Departments of Microbiology and Immunology and Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Sheppard
authors.affiliation: Department of Medical Genetics, RI-MUHC, Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
authors.affiliation: 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.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Vinh
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins / Q000172:deficiency* / Q000235:genetics*; D058365:Candidiasis, Invasive / Q000175:diagnosis / Q000235:genetics / Q000276:immunology*; D020314:Central Nervous System Fungal Infections / Q000175:diagnosis / Q000235:genetics / Q000276:immunology*; D015331:Cohort Studies; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D005260:Female; D005819:Genetic Markers; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000175:diagnosis / Q000235:genetics* / Q000382:microbiology; D008297:Male; D017354:Point Mutation; D011792:Quebec; D060888:Real-Time Polymerase Chain Reaction; D020666:ras-GRF1 / Q000276:immunology* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D053468:CARD Signaling Adaptor Proteins; C505855:CARD9 protein, human; D005819:Genetic Markers; C513039:RASGRF1 protein, human; D020666:ras-GRF1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: CSF2; Caspase recruitment domain-containing protein 9; GM-CSF; Ras protein–specific guanine nucleotide-releasing factor 1; candidiasis; extracellular signal-regulated kinase; spontaneous central nervous system candidiasis