Idiopathic multicentric Castleman disease with novel heterozygous Ile729Met mutation in exon 10 of familial Mediterranean fever gene

Author:

Endo Yushiro1,Koga Tomohiro1,Otaki Hiroki2ORCID,Sasaki Daisuke3,Sumiyoshi Remi1,Furukawa Kaori1,Tanaka Yoshimasa2ORCID,Katsunori Yanagihara3,Kawakami Atsushi1

Affiliation:

1. Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Medical Sciences

2. Center for Bioinformatics and Molecular Medicine, Graduate School of Biomedical Sciences, Nagasaki University

3. Department of Laboratory Medicine, Nagasaki University Hospital, Nagasaki, Japan

Abstract

Abstract Objective While the aetiology of idiopathic multicentric Castleman disease (iMCD) remains unclear, the involvement of autoinflammatory mechanisms has been suggested. Herein we report a Japanese patient with iMCD with a novel heterozygous Ile729Met mutation in exon 10 of the Mediterranean fever (MEFV) gene. Methods We performed genetic analysis via targeted next-generation sequencing analysis and Sanger sequencing and conducted molecular dynamics simulations to investigate the hydrophobic interactions around the 729th amino acid in human pyrin. Results In February 2011, a 59-year-old man was diagnosed with IgG4-related disease at our department based on the findings of cervical and hilar lymphadenopathies, typical lung lesions and cervical lymph node biopsy. The patient was followed up without treatment, as he was asymptomatic. However, he had been experiencing prolonged fatigue and fever with high levels of CRP since June 2017. Axillary lymph node biopsy findings led to the diagnosis of iMCD. He was successfully treated with an IL-6 inhibitor and has been in remission for 12 months. Genetic analyses for hereditary autoinflammatory disease–related genes were performed, revealing a novel heterozygous Ile729Met mutation in exon 10 of the MEFV gene. We identified that this novel mutation significantly altered the local interaction of the human pyrin B30.2 domain by molecular dynamics simulation analysis and experimentally had the potential for inflammasome activation with increased inflammatory cytokines. Conclusion The abnormal function of pyrin due to a mutation in the MEFV gene in this patient may have contributed to the development of MCD by inducing IL-6 production via inflammasome signalling.

Funder

Japan Agency for Medical Research and Development

Publisher

Oxford University Press (OUP)

Subject

Pharmacology (medical),Rheumatology

Reference16 articles.

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2. The clinical spectrum of 94 patients carrying a single mutated MEFV allele;Kone-Paut;Rheumatology (Oxford),2009

3. Mutant ADA2 in vasculopathies;Van Eyck;N Engl J Med,2014

4. Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever;Shinar;J Rheumatol,2000

5. Multiple serum cytokine profiling to identify combinational diagnostic biomarkers in attacks of familial Mediterranean fever;Koga;Medicine (Baltimore),2016

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