Journal
JOURNAL OF CLINICAL IMMUNOLOGY
Volume 39, Issue 1, Pages 75-80Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10875-018-0572-1
Keywords
Interferonopathy; retinoic acid-inducible gene I; Singleton-Merten syndrome; type I interferon
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Funding
- National Institute for Health Research (NIHR) [TRF-2016-09-002]
- National Human Genome Research Institute (WAG)
- NIH Intramural Research Fund [ZIA-AI001220, RO1-N5021328-030]
- NIH Common Fund [RO1OD010944-05]
- NIH R01 grant [AI106912, AI111784]
- European Research Council [GA 309449]
- National Research Agency (France) under the Investments for the Future program [ANR-10-IAHU-01]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI111784, ZIAAI001220, R01AI106912] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [R01OD010944] Funding Source: NIH RePORTER
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PurposeSingleton-Merten syndrome manifests as dental dysplasia, glaucoma, psoriasis, aortic calcification, and skeletal abnormalities including tendon rupture and arthropathy. Pathogenic variants in IFIH1 have previously been associated with the classic Singleton-Merten syndrome, while variants in DDX58 has been described in association with a milder phenotype, which is suggested to have a better prognosis. We studied a family with severe, classic Singleton-Merten syndrome.MethodsWe undertook clinical phenotyping, next-generation sequencing, and functional studies of type I interferon production in patient whole blood and assessedthe type I interferon promoter activity in HEK293 cells transfected with wild-type or mutant DDX58 stimulated with Poly I:C.ResultsWe demonstrate a DDX58 autosomal dominant gain-of-function mutation, with constitutive upregulation of type I interferon.ConclusionsDDX58 mutations may be associated with the classic features of Singleton-Merten syndrome including dental dysplasia, tendon rupture, and severe cardiac sequela.
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