Detection of a rare variant in PSTPIP1 through three generations in a family with an initial diagnosis of FMF/MKD-overlapping phenotype.
Objective The presence of FMF cases without MEFV (MEFV innate immunity regulator, pyrin) pathogenic variants led us to search for other genes' involvement in the disease development. Here, we describe the presence of genetic heterogeneity in a three-generation family with an FMF/mevalonate kinase de...
| Publicado en: | Rheumatology Vol. 62; no. 9; pp. 3188 - 3197 |
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| Autores principales: | , , , , , , , |
| Formato: | pictorial research tables/charts Journal Article |
| Publicado: |
Oxford University Press / USA
Sep2023
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=171352486&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 171352486 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 14620324 DN9 jtl: Rheumatology issn: 14620324 maglogo: N pubinfo: dt: Sep2023 vid: 62 iid: 9 pid: 622 pub: Oxford University Press / USA artinfo: ui: 171352486 171352486 171352486 10.1093/rheumatology/kead044 171352486 ppf: 3188 ppct: 9 formats: tig: atl: Detection of a rare variant in PSTPIP1 through three generations in a family with an initial diagnosis of FMF/MKD-overlapping phenotype. aug: au: Önen, Merve Özkılınç Onat, Umut İ Uğurlu, Serdal Timuçin, Ahmet C Arslan, Devrim Öz Everest, Elif Özdoğan, Huri Turanlı, Eda Tahir affil: Molecular Biology-Genetics and Biotechnology Program, Graduate School of Science, Engineering and Technology, Istanbul Technical University , Istanbul, Turkey sug: subj: Mutation Hereditary Autoinflammatory Diseases Diagnosis Mevalonate Kinase Deficiency Metabolism Phenotype Hereditary Autoinflammatory Diseases Familial and Genetic Human Sequence Analysis Precipitin Tests Molecular Structure Immunoblotting Inflammation Caspases Metabolism Interleukins Metabolism Cytoskeletal Proteins Metabolism Funding Source Descriptive Statistics ab: Objective The presence of FMF cases without MEFV (MEFV innate immunity regulator, pyrin) pathogenic variants led us to search for other genes' involvement in the disease development. Here, we describe the presence of genetic heterogeneity in a three-generation family with an FMF/mevalonate kinase deficiency (MKD)-overlapping phenotype without MEFV/MVK (mevalonate kinase) pathogenic variants. Method Targeted sequencing revealed a rare, fully penetrant variant in PSTPIP1 (p.Arg228Cys, rs781341816). Computational stability analyses of PSTPIP1 protein were performed. PSTPIP1-pyrin protein interaction was examined by immunoprecipitation and immunoblotting in peripheral blood mononuclear cells (PBMCs) of patients and healthy controls. PBMCs were cultured, and inflammation was induced by LPS+ATP treatment, followed by protein level measurements of caspase-1, IL1ß, pyrin and PSTPIP1 in cell lysates and mature caspase-1 and mature IL1ß in supernatants. Results The conserved, rare (GnomAD, 0.000028) PSTPIP1 p.Arg228Cys variant, previously reported in ClinVar as a variant with uncertain significance, showed complete penetrance in the family presenting an autosomal dominant pattern. Computational analyses showed a potentially destabilizing effect of the variant on PSTPIP1 protein. Accordingly, PSTPIP1-pyrin interaction was increased in patients harboring the variant, which resulted in elevated levels of mature caspase-1 and IL1ß in the inflammation-induced patient samples. Conclusions Unlike previously described cases with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA)-associated PSTPIP1 variants, our patients with the p.Arg228Cys variant presented with an FMF/MKD-overlapping phenotype. As additional data on the genetic heterogeneity in the variable clinical spectrum of autoinflammatory syndromes, we suggest that the p.Arg228Cys variant in PSTPIP1 is related to inflammation responses through strong PSTPIP1 -pyrin interaction and pyrin inflammasome activation. pubtype: Academic Journal doctype: pictorial research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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