Abstract

BackgroundMultiple 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.MethodsThe 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.ResultsEleven 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.ConclusionsNovel 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0525-x) contains supplementary material, which is available to authorized users.

Highlights

  • Multiple autoimmune syndrome (MAS), an extreme phenotype of autoimmune disorders, is a very well suited trait to tackle genomic variants of these conditions

  • When three or more autoimmune disease (AD) coexist, the condition is called multiple autoimmune syndrome (MAS), which characterises the best example of polyautoimmunity, and probably the most conspicuous extreme autoimmune phenotype [4] i.e., (1) MAS amalgamates signs and symptoms that are present in several ADs, (2) the MAS signs and symptoms clustering is not random but it outlines the presence of subtypes, (3) in many occurrences, it clusters in families, and (4) major gene effects and the potential location of these MAS major loci have been established [4, 5]

  • Identifying potential population structure After applying principal component analysis (PCA), there was no evidence of stratification effect between cases and controls

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Summary

Introduction

Multiple autoimmune syndrome (MAS), an extreme phenotype of autoimmune disorders, is a very well suited trait to tackle genomic variants of these conditions. It is possible that much of the genetic control of common diseases is due to rare and pathogenic variants with a major effect on the phenotype. The detection of these rare genomic variants harboured in coding regions has shown to be achievable using extreme phenotypes (those exhibiting an unexpected and extreme accumulation of signs and/or symptoms than those expected by the disease’s natural history) and pedigrees segregating exceptional phenotypes [1, 2]. Sjögren’s syndrome (SS), an autoimmune exocrinopathy, is frequently observed in MAS patients [7]

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