Comment on: Pyrin variant E148Q potentiates inflammasome activation and the effect of pathogenic mutations in cis
Year: 2024
Type: letter
Abstract: Dear Editor, I read with great interest the study by Reygaerts et al. [1] on the potential pathogenic role of the E148Q variant in FMF. I was particularly intrigued by the conclusion that the presence of E148Q in cis with M694I may contribute to the autosomal dominant inheritance of the disease. I want to share a recent case I encountered, with the journal readers, which raises some concerns about the study’s conclusions. A 10-year-old boy presented with recurrent fever, arthralgia, skin rash and angioedema. These episodes lasted for 3 days and occurred about twice a month. Despite the atypical symptoms (skin rash and angioedema) and the patient’s Ashkenazi Jewish ancestry, a diagnosis of FMF was proposed. Genetic testing revealed the patient carried two pyrin variants: V726A and E148Q. A therapeutic trial with colchicine was ineffective. He was then referred to my clinic for further evaluation. The patient’s family history revealed similar symptoms in his brother, father and paternal grandmother, while his mother was completely asymptomatic. This suggested an autosomal dominant pattern, which is unusual for FMF. Whole-genome sequencing showed that the symptomatic father did not carry any MEFV mutation, while the asymptomatic mother and brother both carried V726A and E148Q. Given that both children shared the same genotype as their mother, and the father did not carry any mutation, we concluded that the variants were on the same allele in cis (complex allele). This case illustrates a scenario of a recurrent fever syndrome inherited in an autosomal dominant manner, where some patients carry two mutations (V726A and E148Q) in cis that are not associated with the disease. The mother, who carried both mutations, remained asymptomatic, whereas the father, who had similar symptoms, did not carry any MEFV variant. Therefore, the genetic test results in this case were a ‘red herring’. Several lessons from this case are relevant to the study by Reygaerts et al.: In contrast to the study’s findings, E148Q and V726A in cis did not cause disease in our case. It is crucial to determine whether mutations are in trans (biallelic) or cis (complex allele). When in cis, the patients may be considered heterozygotes since they possess a healthy wild-type allele. Approximately 95–98% of heterozygotes are asymptomatic, as seen in the case of the mother [2]. However, we still lack an explanation for why a small percentage of heterozygotes develop full-blown FMF. The study found that the combination of E148Q with V726A in cis was more potent in ASC speck formation in vitro than E148Q with M694I. Yet, the mother, who carried this ‘potent combination’ was asymptomatic. The proposed explanation of a saturation effect in their assay remains speculative. Studies based on in silico, animal or in vitro models do not always reflect the true pathogenesis of FMF in humans. For example, an in-silico tool using PolyPhen-2 predicted that the M694V variant is benign, despite being linked with the most severe clinical outcomes [3]. Similarly, the current study found that B30.2 domain pathogenic mutations did not increase inflammasome formation, while the exon 2 E148Q variant did. These examples highlight the discrepancy between in vitro studies and real-life data on the pathogenicity of MEFV variants. The authors noted that E148Q in trans did not significantly increase inflammasome formation. They claimed that wild-type pyrin does not contribute to inflammasome oligomerization with pyrin harbouring E148Q or E148Q-M694I. Moreover, they also stated that most individuals with E148Q and pathogenic FMF mutations do not develop FMF, which was not supported by their cited references [4] or our observations. Typically, pathogenic exon 10 mutations with E148Q in trans are associated with symptomatic patients, contrary to the study’s in vitro results. The attempt to link E148Q to various polygenic diseases such as IgA vasculitis, ulcerative colitis, Crohn’s disease, Behçet’s disease, recurrent aphthous stomatitis, RA, JIA, and multiple sclerosis appears exaggerated and lacks sufficient evidence. While the study offers potential explanations for the role of E148Q in certain conditions, it does not account for why this variant is benign in most homozygotes cases. It does not explain why FMF is rare in Southeast Asia where the carrier rate of E148Q reaches 25% [5], and why the prevalence of this variant is similar in FMF patients and healthy individuals in some populations [6]. These observations still challenge the pathogenic role of E148Q in FMF. There is a possibility that the pathogenic role attributed to E148Q may result from an unknown surrogate factor, possibly involving epigenetic factors, microbiome changes or small RNAs variations in link with this variant. In conclusion, despite the substantial effort invested in this study, its limitations and the need for some speculative explanations for unexpected results leave the exact role of the E148Q variant an enigma, awaiting further clarification [6–8]. The data underlying this article are available in the article. No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The author has declared no conflicts of interest. Consent: Informed consent was provided for the publication of this article.
Source: Lara D. Veeken
Author: Eldad Ben-Chetrit
Institutions: Hebrew University of Jerusalem, Hadassah Medical Center
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4402665912