New Human Autoinflammatory Disease Identified
By LabMedica International staff writers Posted on 24 Dec 2019 |
Image: Innate immune cells: heterozygous mutations of the RIPK1 caspase-8 cleavage site cause the autoinflammatory disease CRIA syndrome (Photo courtesy of Walter and Eliza Hall Institute)
Autoinflammatory diseases are caused by abnormal activation of the innate immune system, leading to recurrent episodes of fever and inflammation that can damage vital organs.
Scientists from Australia and the USA have discovered and identified the genetic cause of a previously unknown human autoinflammatory disease. They have determined that the autoinflammatory disease, which they termed cleavage-resistant RIPK1-induced autoinflammatory (CRIA) syndrome, is caused by a mutation in a critical cell death component called RIPK1.
Scientists from the Walter and Eliza Hall Institute (Parkville, Australia) and the National Institutes of Health (Bethesda, MD, USA) have described patients from three families with a history of episodic high fevers and painful swollen lymph nodes. The patients, who were diagnosed with a new autoinflammatory disease (CRIA syndrome), had a host of other inflammatory symptoms which began in childhood and continued into their adult years.
The teams sequenced the entire exome of each patient and discovered unique mutations in the exact same amino acid of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in each of the three families. RIPL1is a serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage.
To define the mechanism for this disease, the scientists generated a cleavage-resistant Ripk1D325A mutant mouse strain. Whereas Ripk1−/− mice died post-natally from systemic inflammation, Ripk1D325A/D325A mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner.
Najoua Lalaoui, PhD, the first author of the study, said, “Cell death pathways have developed a series of inbuilt mechanisms that regulate inflammatory signals and cell death, because the alternative is so potentially hazardous. However in this disease, the mutation in RIPK1 is overcoming all the normal checks and balances that exist, resulting in uncontrolled cell death and inflammation.”
The authors concluded that their results demonstrated the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life. The study was published on December 11, 2019 in the journal Nature.
Related Links:
Walter and Eliza Hall Institute
National Institutes of Health
Scientists from Australia and the USA have discovered and identified the genetic cause of a previously unknown human autoinflammatory disease. They have determined that the autoinflammatory disease, which they termed cleavage-resistant RIPK1-induced autoinflammatory (CRIA) syndrome, is caused by a mutation in a critical cell death component called RIPK1.
Scientists from the Walter and Eliza Hall Institute (Parkville, Australia) and the National Institutes of Health (Bethesda, MD, USA) have described patients from three families with a history of episodic high fevers and painful swollen lymph nodes. The patients, who were diagnosed with a new autoinflammatory disease (CRIA syndrome), had a host of other inflammatory symptoms which began in childhood and continued into their adult years.
The teams sequenced the entire exome of each patient and discovered unique mutations in the exact same amino acid of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in each of the three families. RIPL1is a serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage.
To define the mechanism for this disease, the scientists generated a cleavage-resistant Ripk1D325A mutant mouse strain. Whereas Ripk1−/− mice died post-natally from systemic inflammation, Ripk1D325A/D325A mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner.
Najoua Lalaoui, PhD, the first author of the study, said, “Cell death pathways have developed a series of inbuilt mechanisms that regulate inflammatory signals and cell death, because the alternative is so potentially hazardous. However in this disease, the mutation in RIPK1 is overcoming all the normal checks and balances that exist, resulting in uncontrolled cell death and inflammation.”
The authors concluded that their results demonstrated the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life. The study was published on December 11, 2019 in the journal Nature.
Related Links:
Walter and Eliza Hall Institute
National Institutes of Health
Latest Molecular Diagnostics News
- Urine Test to Revolutionize Lyme Disease Testing
- Simple Blood Test Could Enable First Quantitative Assessments for Future Cerebrovascular Disease
- New Genetic Testing Procedure Combined With Ultrasound Detects High Cardiovascular Risk
- Blood Samples Enhance B-Cell Lymphoma Diagnostics and Prognosis
- Blood Test Predicts Knee Osteoarthritis Eight Years Before Signs Appears On X-Rays
- Blood Test Accurately Predicts Lung Cancer Risk and Reduces Need for Scans
- Unique Autoantibody Signature to Help Diagnose Multiple Sclerosis Years before Symptom Onset
- Blood Test Could Detect HPV-Associated Cancers 10 Years before Clinical Diagnosis
- Low-Cost Point-Of-Care Diagnostic to Expand Access to STI Testing
- 18-Gene Urine Test for Prostate Cancer to Help Avoid Unnecessary Biopsies
- Urine-Based Test Detects Head and Neck Cancer
- Blood-Based Test Detects and Monitors Aggressive Small Cell Lung Cancer
- Blood-Based Machine Learning Assay Noninvasively Detects Ovarian Cancer
- Simple PCR Assay Accurately Differentiates Between Small Cell Lung Cancer Subtypes
- Revolutionary T-Cell Analysis Approach Enables Cancer Early Detection
- Single Genetic Test to Accelerate Diagnoses for Rare Developmental Disorders