ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2348

A New Cause of Mendelian Lupus Due to IKZF1 Mutation Underlines the B Cell Landscape Heterogeneity in Monogenic Lupus

Alexandre Belot1,2, Cecile Frachette3, Omarjee Sulliman Ommar2, Anne-Laure Mathieu2, Thibault Andrieu2, Paul Mondier2, Gillian Rice4, Heloise Reumaux5, David Launay6,7, Marc Lambert8,9, Guillaume Lefevre10, Nicole Fabien11, Christophe Malcus12, Isabelle Rouvet13, Emilie Chopin13, Anne-Sophie Michallet14, Thierry Defrance14, Thierry Walzer14 and Yanick J Crow15, 1Pediatric Rheumatology Unit, HFME, Hospices Civils de Lyon, Bron, France, 2U1111, INSERM, Lyon, France, 3Hospices Civils de Lyon, Bron, France, 4Manchester Academic Health Science Centre, Institute of Human Development, University of Manchester, Manchester, United Kingdom, 5Pediatric Rheumatology, CHRU Lille, Lille, France, 6LIRIC, INSERM UMR 995, Lille, France, 7Service de Médecine Interne, Centre National de Référence des Maladies Systémiques Rares, Hôpital Claude Huriez, CHRU Lille, Lille, France, 8Univ. Lille, U995, Lille Inflammation Research International Center (LIRIC), F-59000 Lille, France, Lille, France, 9Medecine Interne Lilloise, Service de médecine interne, Hôpital Claude Huriez, Université Lille II, Lille, France, Lille, France, 10Internal Medicine, Lille University Hospital, Lille, France, 11Immunology Department, UF d'Autoimmunité, Immunology Department, CHU de Lyon HCL- GH Sud, Lyon, France, 12Cellular Immunology Department - Laboratoire d'immunologie cellulaire, Groupement Hospitalier Edouard Herriot, Lyon, France, 13Cellular Biotechnology Department, Centre de biologie et pathologie Est, Hospices civils de Lyon, Lyon, France, 14International Center for Infectiology Research - CIRI, Lyon, France, 15Institut Imagine, Paris, France

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: ,

Session Information

Date: Tuesday, November 7, 2017

Title: Pediatric Rheumatology – Pathogenesis and Genetics Poster

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose:

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.

Methods:

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.

Results:

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.

Conclusion:

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.

Disclosure: A. Belot, None; C. Frachette, None; O. S. Ommar, None; A. L. Mathieu, None; T. Andrieu, None; P. Mondier, None; G. Rice, None; H. Reumaux, None; D. Launay, None; M. Lambert, None; G. Lefevre, None; N. Fabien, None; C. Malcus, None; I. Rouvet, None; E. Chopin, None; A. S. Michallet, None; T. Defrance, None; T. Walzer, None; Y. J. Crow, None.

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 .

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