Genetic Complexity of Autoinflammatory Disorders: The Role of a Rare PSTPIP1 Variant in FMF/MKD-Overlapping Phenotype
In the realm of medical genetics, familial Mediterranean fever (FMF) and mevalonate kinase deficiency (MKD) stand as prominent hereditary autoinflammatory disorders, traditionally associated with pathogenic variants in specific genes like MEFV and MVK. However, our recent study has unveiled a rare genetic variant in the gene PSTPIP1 that challenges the conventional understanding of these disorders, highlighting the complexities of genetic influences on autoinflammatory diseases.
A Rare Genetic Discovery
Our research focused on a three-generation family initially diagnosed with an FMF/MKD-overlapping phenotype but lacking pathogenic variants in the typical MEFV and MVK genes. Through targeted sequencing, we identified a rare variant in PSTPIP1: p.Arg228Cys, notable for its very low frequency (GnomAD, 0.000028) in the general population. This discovery was pivotal, as it suggested alternative genetic pathways influencing autoinflammatory diseases beyond MEFV and MVK pathogenic variants.
Family Background and Genetic Analysis
The family consisted of 4 affected individuals spanning three generations, suggesting a possible autosomal dominant inheritance pattern of the unidentified genetic cause.
The affected family members shared several core symptoms that are indicative of an autoinflammatory response. All four patients experienced recurrent episodes of fever, arthralgia, arthritis abdominal pain, oral ulcers, and tonsillitis.
The family under study was unique due to the presence of autoinflammatory symptoms across three generations but without any known pathogenic variants in the typically implicated MEFV and MVK genes. This unusual presentation led us to explore other genetic contributions.
We employed targeted sequencing, focusing on genes known to be associated with autoinflammatory disorders.
Identification of a Rare Variant: The sequencing revealed a rare, previously under-recognized variant in the PSTPIP1 gene, denoted as p.Arg228Cys. This variant was found to be heterozygous among all affected family members, suggesting its potential role in the disease phenotype.
Multiple investigative techniques were employed to explore the implications of the PSTPIP1 p.Arg228Cys variant to understand its effects on protein structure and function. AlphaFold and other bioinformatics tools predicted that this variant could destabilize the PSTPIP1 protein structure. Sanger sequencing confirmed the variant's presence within affected family members. Further analysis revealed an increased binding affinity between PSTPIP1 and pyrin in cells from patients, as evidenced by immunoprecipitation and immunoblotting, indicating an enhanced interaction that may exacerbate autoinflammatory symptoms. Additionally, inflammatory response analysis using treated PBMCs showed elevated levels of inflammasome components like caspase-1 and IL-1β in patients, suggesting that the variant intensifies inflammatory signaling, correlating with the clinical manifestations of the disorder. These multifaceted approaches underscore the variant's significant impact on cellular mechanisms and disease pathology.
Broader Implications
Our findings are significant for several reasons:
Genetic Heterogeneity in Autoinflammatory Diseases: This research underscores the genetic complexity and heterogeneity underlying autoinflammatory disorders. It challenges the traditional view that only specific genes are involved and opens up possibilities for the involvement of other genetic players like PSTPIP1.
Clinical Diagnosis and Management: The identification of such rare variants can profoundly impact clinical diagnostics and personalized treatment strategies. Recognizing that patients with typical FMF/MKD symptoms might have other underlying genetic causes can lead to more tailored and effective treatments.
Conclusion
Our comprehensive study, traversing three generations of a family exhibiting an FMF/MKD-overlapping phenotype without the typical pathogenic variants in MEFV and MVK, has significantly advanced our understanding of the genetic underpinnings of autoinflammatory diseases. The discovery of a rare, heterozygous variant in the PSTPIP1 gene, p.Arg228Cys, sheds light on the potential complexities and heterogeneity inherent in these disorders. Through detailed protein-protein interaction studies and inflammatory response analysis, we demonstrated that the PSTPIP1p.Arg228Cys variant increases the interaction between PSTPIP1 and pyrin, enhancing inflammasome activity. By expanding our genetic horizons, we can better comprehend, diagnose, and treat the myriad presentations of autoinflammatory diseases, ultimately leading to more precise and effective clinical management.
Reference:
Özkılınç Önen, M., Onat, U. İ., Uğurlu, S., Timuçin, A. C., Öz Arslan, D., Everest, E., ... & Tahir Turanlı, E. (2023). Detection of a rare variant in PSTPIP1 through three generations in a family with an initial diagnosis of FMF/MKD-overlapping phenotype. Rheumatology, 62(9), 3188-3196.
