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Detection of Rare Genomic Variants from Pooled Sequencing Using SPLINTER
Published on: June 23, 2012
Detection of a rare variant in PSTPIP1 through three generations in a family with an initial diagnosis of
Merve Özkılınç Önen1, Umut I Onat2, Serdal Uğurlu3
1Molecular Biology-Genetics and Biotechnology Program, Graduate School of Science, Engineering and Technology, Istanbul Technical University, Istanbul, Turkey.
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.
Insights
A rare PSTPIP1 variant (p.Arg228Cys) causes autoinflammatory disease by enhancing pyrin inflammasome activation, leading to Familial Mediterranean Fever/mevalonate kinase deficiency-overlapping symptoms without MEFV or MVK mutations.
Area of Science:
- Genetics
- Immunology
- Molecular Biology
Background:
- Familial Mediterranean Fever (FMF) can occur without pathogenic variants in the MEFV gene.
- Genetic heterogeneity is suspected in FMF/mevalonate kinase deficiency (MKD) overlapping phenotypes.
- The role of PSTPIP1 variants in autoinflammatory syndromes is being investigated.
Purpose of the Study:
- To investigate the genetic basis of an FMF/MKD-overlapping phenotype in a family without MEFV or MVK variants.
- To identify and characterize novel genetic variants associated with autoinflammatory diseases.
- To elucidate the molecular mechanism linking PSTPIP1 variants to inflammasome activation.
Main Methods:
- Targeted sequencing to identify genetic variants.
- Computational analysis of protein stability.
- Immunoprecipitation and immunoblotting to assess protein interactions.
- In vitro cell culture and stimulation to measure inflammatory markers.
Main Results:
- A rare, fully penetrant PSTPIP1 variant (p.Arg228Cys) was identified, showing autosomal dominant inheritance.
- The PSTPIP1 p.Arg228Cys variant potentially destabilizes the PSTPIP1 protein and increases its interaction with pyrin.
- Inflammation-induced patient samples exhibited elevated levels of caspase-1 and IL-1ß due to enhanced pyrin inflammasome activation.
Conclusions:
- The PSTPIP1 p.Arg228Cys variant is associated with an FMF/MKD-overlapping phenotype.
- This variant contributes to autoinflammation via enhanced PSTPIP1-pyrin interaction and pyrin inflammasome activation.
- PSTPIP1 represents a novel genetic factor in the spectrum of autoinflammatory syndromes.
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