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| Status |
Public on Jun 18, 2021 |
| Title |
Heterozygous OAS1 Gain-of-Function Variants Cause a Polymorphic Autoinflammatory and Immunodeficiency Syndrome |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Oligoadenylate synthase 1 (OAS1) is a type-1 interferon-inducible, intracellular double-stranded RNA (dsRNA) sensor that generates 2'-5'-oligoadenylate (2-5A) to activate RNaseL as a means of antiviral defense. We report four de novo heterozygous OAS1 variants in five patients. Variant OAS1 proteins show dsRNA-independent gain-of-function 2-5A synthetase activity that results in RNaseL-mediated RNA-cleavage, transcriptomic downregulation, and functional impairment and/or apoptosis of monocytes, iPSC-derived macrophages, and B-cells. This leads to a polymorphic syndrome of monocyte, macrophage, and B-cell deficiency characterized by autoinflammation, pulmonary alveolar proteinosis, and hypogammaglobulinemia. RNase-L-inhibition in vitro mitigates, and hematopoietic cell transplantation in vivo corrects the autoinflammatory and immunodeficiency phenotype.
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| Overall design |
iPSC-derived macrophages, poly-A tailed mRNA isolation, library preparation and quantification were performed with NEBNext kits (New England Biolabs, Ipswich, USA) following manufacture’s instructions. Libraries were sequenced on a NextSeq 500 (Illumina, San Diego, USA)
Poly-A selection?based RNA sequencing (RNA-seq) was performed on FACS-sorted OAS1-WT (three different healthy donors (HD), HD1 and HD2 in duplicates) and A76V (in duplicates) CD14 monocytes, CD19 B cells, and CD3 T cells. Libraries were sequenced on a single lane in 100 bp single end mode on a HiSeq1500 instrument (Illumina, San Diego, USA).
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| Contributor(s) |
Magg T, Okano T, Koenig LM, Boehmer DR, Schwartz SL, Inoue K, Heimall J, Licciardi F, Ley-Zaporozhan J, Ferdman RM, Caballero-Oteyza A, Park EN, Calderon BM, Dey D, Kanegane H, Cho K, Montin D, Reiter K, Griese M, Albert MH, Rohlfs M, Gray P, Walz C, Conn GL, Sullivan KE, Klein C, Morio T, Hauck F |
| Citation(s) |
34145065 |
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| Submission date |
Apr 30, 2021 |
| Last update date |
Nov 20, 2021 |
| Contact name |
Thomas Magg |
| E-mail(s) |
thomas.magg@med.uni-muenchen.de
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| Organization name |
Dr. von Haunersches Kinderspital der LMU München
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| Street address |
Lindwurmstr. 2a
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| City |
München |
| ZIP/Postal code |
80337 |
| Country |
Germany |
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| Platforms (2) |
| GPL18460 |
Illumina HiSeq 1500 (Homo sapiens) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (31)
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| Relations |
| BioProject |
PRJNA726563 |
| SRA |
SRP318036 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE173667_OAS1_CD3_CD14_CD19_counts.xlsx |
2.4 Mb |
(ftp)(http) |
XLSX |
| GSE173667_OAS1_RNAseq_iPSC-derived_Macrophages_counts.xlsx |
5.0 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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