Targeted Resequencing and Functional Testing Identifies Low-Frequency Missense Variants in the Gene Encoding GARP as Significant Contributors to Atopic Dermatitis Risk

Gene-mapping studies have consistently identified a susceptibility locus for atopic dermatitis and other inflammatory diseases on chromosome band 11q13.5, with the strongest association observed for a common variant located in an intergenic region between the two annotated genes C11orf30 and LRRC32....

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Published in	Journal of investigative dermatology Vol. 136; no. 12; pp. 2380 - 2386
Main Authors	Manz, Judith, Rodríguez, Elke, ElSharawy, Abdou, Oesau, Eva-Maria, Petersen, Britt-Sabina, Baurecht, Hansjörg, Mayr, Gabriele, Weber, Susanne, Harder, Jürgen, Reischl, Eva, Schwarz, Agatha, Novak, Natalija, Franke, Andre, Weidinger, Stephan
Format	Journal Article
Language	English
Published	United States Elsevier Inc 01.12.2016
Subjects	Adult Case-Control Studies Cells, Cultured Chromosome Mapping Dermatitis, Atopic - drug therapy Dermatitis, Atopic - genetics Dermatitis, Atopic - pathology Disease Progression Female Gene Expression Regulation Genetic Predisposition to Disease Genotype Humans Immunohistochemistry Male Membrane Proteins - genetics Molecular Sequence Data Mutation, Missense Prognosis Real-Time Polymerase Chain Reaction Risk Assessment RNA, Messenger - analysis RNA, Messenger - genetics Sequence Deletion T-Lymphocytes, Regulatory - immunology T-Lymphocytes, Regulatory - pathology PBS C11orf30 AD Treg GARP TGF-β LAP SNV LRRC32 WT
Online Access	Get full text
ISSN	0022-202X 1523-1747 1523-1747
DOI	10.1016/j.jid.2016.07.009

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Abstract	Gene-mapping studies have consistently identified a susceptibility locus for atopic dermatitis and other inflammatory diseases on chromosome band 11q13.5, with the strongest association observed for a common variant located in an intergenic region between the two annotated genes C11orf30 and LRRC32. Using a targeted resequencing approach we identified low-frequency and rare missense mutations within the LRRC32 gene encoding the protein GARP, a receptor on activated regulatory T cells that binds latent transforming growth factor-β. Subsequent association testing in more than 2,000 atopic dermatitis patients and 2,000 control subjects showed a significant excess of these LRRC32 variants in individuals with atopic dermatitis. Structural protein modeling and bioinformatic analysis predicted a disruption of protein transport upon these variants, and overexpression assays in CD4+CD25– T cells showed a significant reduction in surface expression of the mutated protein. Consistently, flow cytometric (FACS) analyses of different T-cell subtypes obtained from atopic dermatitis patients showed a significantly reduced surface expression of GARP and a reduced conversion of CD4+CD25– T cells into regulatory T cells, along with lower expression of latency-associated protein upon stimulation in carriers of the LRRC32 A407T variant. These results link inherited disturbances of transforming growth factor-β signaling with atopic dermatitis risk.
AbstractList	Gene-mapping studies have consistently identified a susceptibility locus for atopic dermatitis and other inflammatory diseases on chromosome band 11q13.5, with the strongest association observed for a common variant located in an intergenic region between the two annotated genes C11orf30 and LRRC32. Using a targeted resequencing approach we identified low-frequency and rare missense mutations within the LRRC32 gene encoding the protein GARP, a receptor on activated regulatory T cells that binds latent transforming growth factor-β. Subsequent association testing in more than 2,000 atopic dermatitis patients and 2,000 control subjects showed a significant excess of these LRRC32 variants in individuals with atopic dermatitis. Structural protein modeling and bioinformatic analysis predicted a disruption of protein transport upon these variants, and overexpression assays in CD4+CD25- T cells showed a significant reduction in surface expression of the mutated protein. Consistently, flow cytometric (FACS) analyses of different T-cell subtypes obtained from atopic dermatitis patients showed a significantly reduced surface expression of GARP and a reduced conversion of CD4+CD25- T cells into regulatory T cells, along with lower expression of latency-associated protein upon stimulation in carriers of the LRRC32 A407T variant. These results link inherited disturbances of transforming growth factor-β signaling with atopic dermatitis risk.Gene-mapping studies have consistently identified a susceptibility locus for atopic dermatitis and other inflammatory diseases on chromosome band 11q13.5, with the strongest association observed for a common variant located in an intergenic region between the two annotated genes C11orf30 and LRRC32. Using a targeted resequencing approach we identified low-frequency and rare missense mutations within the LRRC32 gene encoding the protein GARP, a receptor on activated regulatory T cells that binds latent transforming growth factor-β. Subsequent association testing in more than 2,000 atopic dermatitis patients and 2,000 control subjects showed a significant excess of these LRRC32 variants in individuals with atopic dermatitis. Structural protein modeling and bioinformatic analysis predicted a disruption of protein transport upon these variants, and overexpression assays in CD4+CD25- T cells showed a significant reduction in surface expression of the mutated protein. Consistently, flow cytometric (FACS) analyses of different T-cell subtypes obtained from atopic dermatitis patients showed a significantly reduced surface expression of GARP and a reduced conversion of CD4+CD25- T cells into regulatory T cells, along with lower expression of latency-associated protein upon stimulation in carriers of the LRRC32 A407T variant. These results link inherited disturbances of transforming growth factor-β signaling with atopic dermatitis risk. Gene-mapping studies have consistently identified a susceptibility locus for atopic dermatitis and other inflammatory diseases on chromosome band 11q13.5, with the strongest association observed for a common variant located in an intergenic region between the two annotated genes C11orf30 and LRRC32. Using a targeted resequencing approach we identified low-frequency and rare missense mutations within the LRRC32 gene encoding the protein GARP, a receptor on activated regulatory T cells that binds latent transforming growth factor-β. Subsequent association testing in more than 2,000 atopic dermatitis patients and 2,000 control subjects showed a significant excess of these LRRC32 variants in individuals with atopic dermatitis. Structural protein modeling and bioinformatic analysis predicted a disruption of protein transport upon these variants, and overexpression assays in CD4 CD25 T cells showed a significant reduction in surface expression of the mutated protein. Consistently, flow cytometric (FACS) analyses of different T-cell subtypes obtained from atopic dermatitis patients showed a significantly reduced surface expression of GARP and a reduced conversion of CD4 CD25 T cells into regulatory T cells, along with lower expression of latency-associated protein upon stimulation in carriers of the LRRC32 A407T variant. These results link inherited disturbances of transforming growth factor-β signaling with atopic dermatitis risk. Gene-mapping studies have consistently identified a susceptibility locus for atopic dermatitis and other inflammatory diseases on chromosome band 11q13.5, with the strongest association observed for a common variant located in an intergenic region between the two annotated genes C11orf30 and LRRC32. Using a targeted resequencing approach we identified low-frequency and rare missense mutations within the LRRC32 gene encoding the protein GARP, a receptor on activated regulatory T cells that binds latent transforming growth factor-β. Subsequent association testing in more than 2,000 atopic dermatitis patients and 2,000 control subjects showed a significant excess of these LRRC32 variants in individuals with atopic dermatitis. Structural protein modeling and bioinformatic analysis predicted a disruption of protein transport upon these variants, and overexpression assays in CD4+CD25– T cells showed a significant reduction in surface expression of the mutated protein. Consistently, flow cytometric (FACS) analyses of different T-cell subtypes obtained from atopic dermatitis patients showed a significantly reduced surface expression of GARP and a reduced conversion of CD4+CD25– T cells into regulatory T cells, along with lower expression of latency-associated protein upon stimulation in carriers of the LRRC32 A407T variant. These results link inherited disturbances of transforming growth factor-β signaling with atopic dermatitis risk.
Author	Oesau, Eva-Maria Franke, Andre Rodríguez, Elke Reischl, Eva ElSharawy, Abdou Baurecht, Hansjörg Novak, Natalija Petersen, Britt-Sabina Weber, Susanne Mayr, Gabriele Manz, Judith Harder, Jürgen Weidinger, Stephan Schwarz, Agatha
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Keywords	PBS C11orf30 AD Treg GARP TGF-β LAP SNV LRRC32 WT
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Snippet	Gene-mapping studies have consistently identified a susceptibility locus for atopic dermatitis and other inflammatory diseases on chromosome band 11q13.5, with...
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SubjectTerms	Adult Case-Control Studies Cells, Cultured Chromosome Mapping Dermatitis, Atopic - drug therapy Dermatitis, Atopic - genetics Dermatitis, Atopic - pathology Disease Progression Female Gene Expression Regulation Genetic Predisposition to Disease Genotype Humans Immunohistochemistry Male Membrane Proteins - genetics Molecular Sequence Data Mutation, Missense Prognosis Real-Time Polymerase Chain Reaction Risk Assessment RNA, Messenger - analysis RNA, Messenger - genetics Sequence Deletion T-Lymphocytes, Regulatory - immunology T-Lymphocytes, Regulatory - pathology
Title	Targeted Resequencing and Functional Testing Identifies Low-Frequency Missense Variants in the Gene Encoding GARP as Significant Contributors to Atopic Dermatitis Risk
URI	https://dx.doi.org/10.1016/j.jid.2016.07.009 https://www.ncbi.nlm.nih.gov/pubmed/27448748 https://www.proquest.com/docview/1826733196
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