Novel and rare functional genomic variants in multiple autoimmune syndrome and Sjögren's syndrome

Johar, Angad S., Mastronardi, Claudio, Rojas-Villarraga, Adriana, Patel, Hardip R., Chuah, Aaron, Peng, Kaiman, Higgins, Angela, Milburn, Peter, Palmer, Stephanie, Silva-Lara, Maria Fernanda, Velez, Jorge I., Andrews, Dan, Field, Matthew, Huttley, Gavin, Goodnow, Chris, Anaya, Juan-Manuel, and Arcos-Burgos, Mauricio (2015) Novel and rare functional genomic variants in multiple autoimmune syndrome and Sjögren's syndrome. Journal of Translational Medicine, 13 (173). pp. 1-11.

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Abstract

Background: Multiple autoimmune syndrome (MAS), an extreme phenotype of autoimmune disorders, is a very well suited trait to tackle genomic variants of these conditions. Whole exome sequencing (WES) is a widely used strategy for detection of protein coding and splicing variants associated with inherited diseases.

Methods: The DNA of eight patients affected by MAS [all of whom presenting with Sjögren's syndrome (SS)], four patients affected by SS alone and 38 unaffected individuals, were subject to WES. Filters to identify novel and rare functional (pathogenic–deleterious) homozygous and/or compound heterozygous variants in these patients and controls were applied. Bioinformatics tools such as the Human gene connectome as well as pathway and network analysis were applied to test overrepresentation of genes harbouring these variants in critical pathways and networks involved in autoimmunity.

Results: Eleven novel and rare functional variants were identified in cases but not in controls, harboured in: MACF1, KIAA0754, DUSP12, ICA1, CELA1, LRP1/STAT6, GRIN3B, ANKLE1, TMEM161A, and FKRP. These were subsequently subject to network analysis and their functional relatedness to genes already associated with autoimmunity was evaluated. Notably, the LRP1/STAT6 novel mutation was homozygous in one MAS affected patient and heterozygous in another. LRP1/STAT6 disclosed the strongest plausibility for autoimmunity. LRP1/STAT6 are involved in extracellular and intracellular anti-inflammatory pathways that play key roles in maintaining the homeostasis of the immune system. Further; networks, pathways, and interaction analyses showed that LRP1 is functionally related to the HLA-B and IL10 genes and it has a substantial impact within immunological pathways and/or reaction to bacterial and other foreign proteins (phagocytosis, regulation of phospholipase A2 activity, negative regulation of apoptosis and response to lipopolysaccharides). Further, ICA1 and STAT6 were also closely related to AIRE and IRF5, two very well known autoimmunity genes.

Conclusions: Novel and rare exonic mutations that may account for autoimmunity were identified. Among those, the LRP1/STAT6 novel mutation has the strongest case for being categorised as potentially causative of MAS given the presence of intriguing patterns of functional interaction with other major genes shaping autoimmunity.

Item ID: 43586
Item Type: Article (Research - C1)
ISSN: 1479-5876
Keywords: autoimmune diseases; polyautoimmunity; multiple autoimmune syndrome; Sjögren's syndrome; genetics; whole exome sequencing; extreme phenotypes
Additional Information:

© Johar et al. 2015. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Funders: Universidad del Rosario
Date Deposited: 30 May 2016 02:49
FoR Codes: 06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060102 Bioinformatics @ 25%
06 BIOLOGICAL SCIENCES > 0604 Genetics > 060408 Genomics @ 25%
11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110706 Immunogenetics (incl Genetic Immunology) @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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