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

Journal of Translational Medicine

Mauricio Arcos-Burgos⁵  Juan-Manuel Anaya¹  Chris Goodnow⁴  Gavin Huttley²  Matthew Field⁴  Dan Andrews⁴  Jorge I Velez⁵  Maria Fernanda Silva-Lara⁵  Stephanie Palmer²  Peter Milburn²  Angela Higgins²  Kaiman Peng²  Aaron Chuah³  Hardip R Patel³  Adriana Rojas-Villarraga¹  Claudio Mastronardi⁵  Angad S Johar⁵ 

[1] Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia;Biomolecular Resource Facility, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia;Genome Discovery Unit, Genome Biology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia;Immunogenomics and Bioinformatics Group, Immunology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia;Genomics and Predictive Medicine, Genome Biology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia

关键词: Extreme phenotypes;    Whole exome sequencing;    Genetics;    Sjögren’s syndrome;    Multiple autoimmune syndrome;    Polyautoimmunity;    Autoimmune diseases;   

Others  :  1233505
DOI  :  10.1186/s12967-015-0525-x

 received in 2015-02-25, accepted in 2015-05-08,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Johar et al.

【 图 表 】

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