Noam Jacob1,2, Sonya S Dasharathy1, Viet Bui1,3, Jihane N Benhammou1,2, Wayne W Grody4,5, Ram Raj Singh1,3,6,7,5, Joseph R Pisegna8,9. 1. UCLA Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at University of California at Los Angeles (UCLA), Los Angeles, CA, 90095, USA. 2. Division of Gastroenterology, Hepatology and Parenteral Nutrition, Department of Veterans Affairs, David Geffen School of Medicine at UCLA, VA Greater Los Angeles Healthcare System (691/111C), 11301 Wilshire Blvd., Los Angeles, CA, 90073, USA. 3. Autoimmunity and Tolerance Laboratory, Division of Rheumatology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA. 4. Departments of Human Genetics and Pediatrics, and the UCLA Clinical Genomics Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA. 5. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA. 6. Molecular Toxicology Interdepartmental Program, UCLA, Los Angeles, CA, 90095, USA. 7. Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, 90095, USA. 8. Division of Gastroenterology, Hepatology and Parenteral Nutrition, Department of Veterans Affairs, David Geffen School of Medicine at UCLA, VA Greater Los Angeles Healthcare System (691/111C), 11301 Wilshire Blvd., Los Angeles, CA, 90073, USA. jpisegna@ucla.edu. 9. Departments of Human Genetics and Pediatrics, and the UCLA Clinical Genomics Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA. jpisegna@ucla.edu.
Abstract
BACKGROUND: Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a group of cytoplasmic sensors that survey danger signals released by invading pathogens or damaged tissue. Mutations in the NLRP subfamily affect pro-inflammatory mediators and cause nonspecific systemic symptoms. AIMS: We sought to identify a potential genetic etiology of an inflammatory syndrome in a patient that presented with an atypical multisystem illness with carcinoid syndrome as well as atopic and autoimmune features. METHODS: Exome sequencing was performed using the Agilent SureSelect Clinical Research Exome XT kit on an Illumina HiSeq 2500. Longitudinal monitoring of pro-inflammatory cytokines was performed. RESULTS: We identified a novel variant (heterozygous c.536C > T [p.Thr179Ile]) in the NLRP12 gene in a 63-year-old woman and her daughter, who presented with an unusual clinical syndrome that differs from autoinflammatory disorders previously reported in association with the NLRP subfamily gene mutations. This NLRP12 variant was predicted to be pathogenic by functional analysis through Hidden Markov Models (FATHMM). Both the mother and the daughter had episodes of abdominal pain, fever, diarrhea, skin rash, hypothyroidism, and elevated urine 5-hydroxyindoleacetic acid (5-HIAA) levels. The proband also had elevated serum levels of pro-inflammatory (IL-1β, IL-6, IL-12, and TNF-α), Th1 (IL-2, IFN-γ), and Th2 (IL-4, IL-5, IL-13) cytokines, but not of Th17 (IL-17) and IL-10. CONCLUSION: This report adds to the expanding spectrum of clinical manifestations attributed to the NLRP subfamily gene variants and suggests a role of NLRP12 in the regulation of multiple cytokines.
BACKGROUND: Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a group of cytoplasmic sensors that survey danger signals released by invading pathogens or damaged tissue. Mutations in the NLRP subfamily affect pro-inflammatory mediators and cause nonspecific systemic symptoms. AIMS: We sought to identify a potential genetic etiology of an inflammatory syndrome in a patient that presented with an atypical multisystem illness with carcinoid syndrome as well as atopic and autoimmune features. METHODS: Exome sequencing was performed using the Agilent SureSelect Clinical Research Exome XT kit on an Illumina HiSeq 2500. Longitudinal monitoring of pro-inflammatory cytokines was performed. RESULTS: We identified a novel variant (heterozygous c.536C > T [p.Thr179Ile]) in the NLRP12 gene in a 63-year-old woman and her daughter, who presented with an unusual clinical syndrome that differs from autoinflammatory disorders previously reported in association with the NLRP subfamily gene mutations. This NLRP12 variant was predicted to be pathogenic by functional analysis through Hidden Markov Models (FATHMM). Both the mother and the daughter had episodes of abdominal pain, fever, diarrhea, skin rash, hypothyroidism, and elevated urine 5-hydroxyindoleacetic acid (5-HIAA) levels. The proband also had elevated serum levels of pro-inflammatory (IL-1β, IL-6, IL-12, and TNF-α), Th1 (IL-2, IFN-γ), and Th2 (IL-4, IL-5, IL-13) cytokines, but not of Th17 (IL-17) and IL-10. CONCLUSION: This report adds to the expanding spectrum of clinical manifestations attributed to the NLRP subfamily gene variants and suggests a role of NLRP12 in the regulation of multiple cytokines.
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