Session Title: Pediatric Rheumatology – Pathogenesis and Genetics Poster
Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Next generation sequencing (NGS) represents a revolution in the field of molecular medicine, and offers a new approach to deciphering the pathogenesis of complex diseases. One hypothesized that patients with early-onset lupus may be carrying genetic mutation responsible for the autoimmune condition. We have in the past described a B cell-related Mendelian form of lupus due to a deficiency of PKCδ. Here, we identified and characterized a new B cell-related Mendelian lupus secondary to IKZF1 mutation and compared this novel monogenic disease with PKCδ deficiency.
We designed a NGS panel comprising 200 genes including proven disease-associated as well as prospective candidate genes, and analyzed 131 patients.
We identified a family with three affected patients carrying a new mutation in IKZF1. We set up functional assays including oligonucleotide pulldown assay, B cell phosphorylation and deep B cell immunophenotyping by mass cytometry.
We have identified a heterozygous missense mutation in IKZF1 c.359A>T in three affected patients in a single family. IKZF1 encodes IKAROS, a key transcriptional factor for B cell development. The patients did not display any reccurent infection and IgG level was normal. Functional assays showed that stability was not impaired, but DNA-binding was partially impacted for mutant IKAROS. We performed mass cytometry comparing SLE patients carrying PRKCD and IKZF1 mutation. We identified B cell clusters and unsupervised analysis underlined the wide differences between two monogenic diseases leading to SLE.
Ikaros deficiency reveals that monogenic lupus occurs under various B cell anomalies underlining that lupus should be considered as a syndrome more than a single homogenous disease.
To cite this abstract in AMA style:Belot A, Frachette C, Ommar OS, Mathieu AL, Andrieu T, Mondier P, Rice G, Reumaux H, Launay D, Lambert M, Lefevre G, Fabien N, Malcus C, Rouvet I, Chopin E, Michallet AS, Defrance T, Walzer T, Crow YJ. A New Cause of Mendelian Lupus Due to IKZF1 Mutation Underlines the B Cell Landscape Heterogeneity in Monogenic Lupus [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/a-new-cause-of-mendelian-lupus-due-to-ikzf1-mutation-underlines-the-b-cell-landscape-heterogeneity-in-monogenic-lupus/. Accessed January 20, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-new-cause-of-mendelian-lupus-due-to-ikzf1-mutation-underlines-the-b-cell-landscape-heterogeneity-in-monogenic-lupus/