Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: To identify new genes/pathways associated with autoinflammatory phenotype.
Methods: We screened genomic variations by whole exome sequencing in 3 families presented with autoinflammatory findings despite negative results for known autoinflammatory gene mutations. A systematic search was carried out specifically for identification of deleterious genetic variants in genes involved in novel inflammatory pathways.
Results: We identified a deleterious mutation in the AGBL3 (ATP/GTP binding protein-like 3) gene, in a consanguineous family of Assyrian origin. Index case, now 22-year-old male, presented to our outpatient clinic with recurrent attacks of fever, urticarial rash on the extremities and trunk, conjunctival injections and arthralgia. His attacks started when he was 13, and two to three day lasting attacks recurred more frequently during warm weather conditions or following hot baths. He had highly elevated CRP and ESR during attacks, but his acute phase response did not return to normal values in between the flares. Low C3 and C4 values were also observed during asymptomatic periods. He responded partially to corticosteroids as well as canakinumab and anakinra treatments, and he is currently on low dose steroids and 200 mg/day anakinra. Whole exome sequencing revealed homozygous c.769C>T mutation in AGBL3 gene, which results in early termination of the protein (p.Gln257Ter) and deletion of carboxypeptidase domain. This protein belongs to metallocarboxypeptidases that mediate both deglutamylation and deaspartylation of target proteins. AGBL3 is suggested to catalyze the deglutamylation of polyglutamate side chains, especially in proteins such as tubulins. Also, STRING search revealed interaction of AGBL3 with complement regulatory proteins, such as CD46, CD55, and CD59, which are potent inhibitors of the complement membrane attack complex.
We searched databases from Turkey and other sources, and we could not identify this variant in other individuals.
Conclusion: This study identifies the AGBL3 metallocarboxypeptidase gene as a potential autoinflammatory gene involved in a novel pathway, and its loss of function mutations may result in a potent innate inflammatory response associated with lower complement levels and a partial response to IL-1 blockade.
To cite this abstract in AMA style:Gül A, Abaci N, Sirma Ekmekci S. New Autoinflammatory Phenotype Associated with Homozygous AGBL3 Variant [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/new-autoinflammatory-phenotype-associated-with-homozygous-agbl3-variant/. Accessed September 28, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/new-autoinflammatory-phenotype-associated-with-homozygous-agbl3-variant/