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

Angad S. Johar, Claudio Mastronardi, Adriana Rojas-Villarraga, Hardip R. Patel, Aaron Chuah, Kaiman Peng, Angela Higgins, Peter Milburn, Stephanie Palmer, Maria Fernanda Silva-Lara, Jorge I. Velez, Dan Andrews, Matthew Field, Gavin Huttley, Chris Goodnow, Juan Manuel Anaya, Mauricio Arcos-Burgos

Resultado de la investigación: Contribución a RevistaArtículo

15 Citas (Scopus)

Resumen

© 2015 Johar et al.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.
Idioma originalEnglish (US)
PublicaciónJournal of Translational Medicine
DOI
EstadoPublished - jun 2 2015

Huella dactilar

Sjogren's Syndrome
Autoimmunity
Genes
Exome
Electric network analysis
Mutation
Connectome
Protein Splicing
Critical Pathways
HLA-B Antigens
Immune system
Phospholipases A2
Bioinformatics
Computational Biology
Phagocytosis
Interleukin-10
Lipopolysaccharides
Immune System
Proteins
Homeostasis

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Johar, A. S., Mastronardi, C., Rojas-Villarraga, A., Patel, H. R., Chuah, A., Peng, K., ... Arcos-Burgos, M. (2015). Novel and rare functional genomic variants in multiple autoimmune syndrome and Sjögren's syndrome. Journal of Translational Medicine. https://doi.org/10.1186/s12967-015-0525-x
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 ; Arcos-Burgos, Mauricio. / Novel and rare functional genomic variants in multiple autoimmune syndrome and Sjögren's syndrome. En: Journal of Translational Medicine. 2015.
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title = "Novel and rare functional genomic variants in multiple autoimmune syndrome and Sj{\"o}gren's syndrome",
abstract = "{\circledC} 2015 Johar et al.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 Sj{\"o}gren'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.",
author = "Johar, {Angad S.} and Claudio Mastronardi and Adriana Rojas-Villarraga and Patel, {Hardip R.} and Aaron Chuah and Kaiman Peng and Angela Higgins and Peter Milburn and Stephanie Palmer and Silva-Lara, {Maria Fernanda} and Velez, {Jorge I.} and Dan Andrews and Matthew Field and Gavin Huttley and Chris Goodnow and Anaya, {Juan Manuel} and Mauricio Arcos-Burgos",
year = "2015",
month = "6",
day = "2",
doi = "10.1186/s12967-015-0525-x",
language = "English (US)",
journal = "Journal of Translational Medicine",
issn = "1479-5876",
publisher = "BioMed Central",

}

Johar, AS, Mastronardi, C, Rojas-Villarraga, A, Patel, HR, Chuah, A, Peng, K, Higgins, A, Milburn, P, Palmer, S, Silva-Lara, MF, Velez, JI, Andrews, D, Field, M, Huttley, G, Goodnow, C, Anaya, JM & Arcos-Burgos, M 2015, 'Novel and rare functional genomic variants in multiple autoimmune syndrome and Sjögren's syndrome', Journal of Translational Medicine. https://doi.org/10.1186/s12967-015-0525-x

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; Arcos-Burgos, Mauricio.

En: Journal of Translational Medicine, 02.06.2015.

Resultado de la investigación: Contribución a RevistaArtículo

TY - JOUR

T1 - Novel and rare functional genomic variants in multiple autoimmune syndrome and Sjögren's syndrome

AU - Johar, Angad S.

AU - Mastronardi, Claudio

AU - Rojas-Villarraga, Adriana

AU - Patel, Hardip R.

AU - Chuah, Aaron

AU - Peng, Kaiman

AU - Higgins, Angela

AU - Milburn, Peter

AU - Palmer, Stephanie

AU - Silva-Lara, Maria Fernanda

AU - Velez, Jorge I.

AU - Andrews, Dan

AU - Field, Matthew

AU - Huttley, Gavin

AU - Goodnow, Chris

AU - Anaya, Juan Manuel

AU - Arcos-Burgos, Mauricio

PY - 2015/6/2

Y1 - 2015/6/2

N2 - © 2015 Johar et al.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.

AB - © 2015 Johar et al.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.

U2 - 10.1186/s12967-015-0525-x

DO - 10.1186/s12967-015-0525-x

M3 - Article

JO - Journal of Translational Medicine

JF - Journal of Translational Medicine

SN - 1479-5876

ER -