SAT0597 New autoinflammatory phenotype manifesting as hypocomplementemic urticarial vasculitis and associated with homozygous agbl3 variant
Authors: A. Gül, N. Abaci, S. Sirma Ekmekci
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Autoinflammatory disorders are primarily associated with inborn errors of the innate immune system, but some of them are also developing autoimmune features. <h3>Objectives</h3> To define a new autoinflammatory phenotype in a patient with inflammatory attacks manifesting as hypocomplementemic urticarial vasculitis and to identify responsible gene/pathway. <h3>Methods</h3> Clinical manifestations of the index case and his family history were carefully searched and blood samples were collected from the index case and his both parents. Genomic variations were screened by whole exome sequencing, and a systematic search was carried out specifically for identification of deleterious genetic variants in genes involved in novel inflammatory pathways. <h3>Results</h3> The index case was coming from a consanguineous family of Assyrian origin, who is now 22-year-old male. He presented to our outpatient clinic with recurrent attacks of fever, urticarial rash on the extremities and trunk, conjunctival injections and arthralgia, without a trigger or more frequently following an infection. His attacks started when he was 13, and two to three days 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. His ANA test became positive during the course of his disease, with an increasing titer in the last year. He responded partially to corticosteroids as well as canakinumab and anakinra treatments, and he is currently on low dose steroids and 100 to 200 mg/day anakinra. Whole exome sequencing revealed a deleterious homozygous c.769C&gt;T mutation in AGBL3 (ATP/GTP binding protein-like 3) gene, which results in early termination of the protein (p.Gln257Ter) and deletion of the functional carboxypeptidase domain. This protein belongs to metallocarboxypeptidases that mediate both deglutamylation and deaspartylation of target proteins. AGBL3 is suggested to catalyse the deglutamylation of polyglutamate side chains, especially in proteins such as tubulins. Also, STRING search revealed the 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 including 1000 Genomes Project data, and we could not identify this variant in other individuals. <h3>Conclusions</h3> This study identifies the AGBL3 metallocarboxypeptidase gene as a potential autoinflammatory gene involved in a novel pathway and possibly associated with hypocomplementemic urticarial vasculitis phenotype. Previously, DNASE1L3 mutations have been associated with hypocomplementemic urticarial vasculitis and systemic lupus erythematosus phenotype. The loss of function mutation in the AGBL3 may result in a potent innate inflammatory response as well as autoimmunity through a new pathway, which is resulting in lower complement levels and ANA positivity along with recurrent inflammatory episodes. This complex phenotype explains a partial response to the IL-1 blockade, and further studies in patients/families with a similar phenotype are needed. <h3>Disclosure of Interest</h3> None declared