دورية أكاديمية
أعرض في EDS

Alternative Splicing Rescues Loss of Common Gamma Chain Function and Results in IL-21R-like Deficiency.

التفاصيل البيبلوغرافية
العنوان: Alternative Splicing Rescues Loss of Common Gamma Chain Function and Results in IL-21R-like Deficiency.
المؤلفون: Illig D; Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Lindwurmstrasse 4, 80337, Munich, Germany., Navratil M; Department of Pulmonology, Allergology, Rheumatology and Clinical Immunology, Children's Hospital Zagreb, Zagreb, Croatia.; School of Medicine, University J.J. Strossmayer, Osijek, Croatia., Kelečić J; Department of Pediatrics, Division of Clinical Immunology, Allergology, Respiratory Diseases and Rheumatology, University Hospital Centre Zagreb, Kišpatićeva 12, Zagreb, 10000, Croatia., Conca R; Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Lindwurmstrasse 4, 80337, Munich, Germany., Hojsak I; School of Medicine, University J.J. Strossmayer, Osijek, Croatia.; Referral Center for Pediatric Gastroenterology and Nutrition, Children's Hospital Zagreb, Zagreb, Croatia.; School of Medicine, University of Zagreb, Zagreb, Croatia., Jadrešin O; Referral Center for Pediatric Gastroenterology and Nutrition, Children's Hospital Zagreb, Zagreb, Croatia., Ćorić M; Department of Pathology and Cytology, University Hospital Centre Zagreb, Zagreb, Croatia., Vuković J; Division of Pediatric Gastroenterology, Hepatology and Nutrition, University Hospital Centre Zagreb, Zagreb, Croatia., Rohlfs M; Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Lindwurmstrasse 4, 80337, Munich, Germany., Hollizeck S; Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Lindwurmstrasse 4, 80337, Munich, Germany., Bohne J; Institute for Virology, Hannover Medical School, Hannover, Germany., Klein C; Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Lindwurmstrasse 4, 80337, Munich, Germany., Kotlarz D; Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Lindwurmstrasse 4, 80337, Munich, Germany. daniel.kotlarz@med.uni-muenchen.de.
المصدر: Journal of clinical immunology [J Clin Immunol] 2019 Feb; Vol. 39 (2), pp. 207-215. Date of Electronic Publication: 2019 Mar 21.
نوع المنشور: Case Reports; Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Springer Country of Publication: Netherlands NLM ID: 8102137 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-2592 (Electronic) Linking ISSN: 02719142 NLM ISO Abbreviation: J Clin Immunol Subsets: MEDLINE
أسماء مطبوعة: Publication: Amsterdam : Springer
Original Publication: New York : Plenum, c1981-
مواضيع طبية MeSH: Interleukin-21 Receptor alpha Subunit/*genetics , Severe Combined Immunodeficiency/*genetics, Alternative Splicing ; B-Lymphocytes/immunology ; Child, Preschool ; Cholangitis/genetics ; Cholangitis/immunology ; Croatia ; Cryptosporidiosis/genetics ; Cryptosporidiosis/immunology ; Diarrhea/genetics ; Diarrhea/immunology ; Humans ; Interleukin-21 Receptor alpha Subunit/deficiency ; Interleukin-21 Receptor alpha Subunit/immunology ; Male ; Respiratory Tract Infections/genetics ; Respiratory Tract Infections/immunology ; Severe Combined Immunodeficiency/immunology
مستخلص: Inborn errors in interleukin 2 receptor, gamma (IL2RG) perturb signaling of the common gamma chain family cytokines and cause severe combined immunodeficiency (SCID). Here, we report two brothers suffering from chronic cryptosporidiosis, severe diarrhea, and cholangitis. Pan T, B, and NK cell numbers were normal, but immunophenotyping revealed defective B cell differentiation. Using whole exome sequencing, we identified a base pair deletion in the first exon of IL2RG predicted to cause a frameshift and premature stop. However, flow cytometry revealed normal surface expression of the IL-2Rγ chain. While IL-2, IL-7, and IL-15 signaling showed only mild defects of STAT5 phosphorylation in response to the respective cytokines, IL-4- and IL-21-induced phosphorylation of STAT3 and STAT6 was markedly reduced. Examination of RNA isoforms detected alternative splicing downstream of IL2RG exon 1 in both patients resulting in resolution of the predicted frameshift and 16 mutated amino acids. In silico modeling suggested that the IL-2Rγ mutation reduces the stabilization of IL-4 and IL-21 cytokine binding by affecting the N-terminal domain of the IL-2Rγ. Thus, our study shows that IL2RG deficiency can be associated with differential signaling defects. Confounding effects of alternative splicing may partially rescue genetic defects and should be considered in patients with inborn errors of immunity.
References: J Pediatr. 1993 Oct;123(4):564-72. (PMID: 8410508)
Blood. 1999 Jan 15;93(2):607-12. (PMID: 9885222)
N Engl J Med. 1996 Nov 21;335(21):1563-7. (PMID: 8900089)
Clin Immunol. 2011 Oct;141(1):73-82. (PMID: 21664875)
Structure. 2009 Jan 14;17(1):54-65. (PMID: 19141282)
Clin Exp Immunol. 2000 Nov;122(2):143-9. (PMID: 11091267)
Nat Rev Immunol. 2009 Jul;9(7):480-90. (PMID: 19543225)
Annu Rev Immunol. 2004;22:625-55. (PMID: 15032591)
J Pediatr. 1997 Mar;130(3):378-87. (PMID: 9063412)
Cell. 2008 Jan 25;132(2):259-72. (PMID: 18243101)
Blood. 1997 Mar 15;89(6):1968-77. (PMID: 9058718)
Eur J Immunol. 1997 Jan;27(1):116-21. (PMID: 9022007)
Blood. 1995 Jan 1;85(1):38-42. (PMID: 7803808)
Blood. 2008 Sep 1;112(5):1872-5. (PMID: 18559672)
Blood. 2008 Nov 15;112(10):4090-7. (PMID: 18728247)
Immunity. 1995 Apr;2(4):331-9. (PMID: 7719938)
Nat Immunol. 2012 Dec;13(12):1187-95. (PMID: 23104097)
Bioessays. 2008 Jul;30(7):683-91. (PMID: 18536038)
Science. 2005 Nov 18;310(5751):1159-63. (PMID: 16293754)
PLoS One. 2017 Jun 1;12(6):e0178700. (PMID: 28570605)
Eur J Immunol. 2014 Oct;44(10):3129-40. (PMID: 25042067)
Biochem Biophys Res Commun. 2003 Jan 10;300(2):291-6. (PMID: 12504082)
J Exp Med. 2013 Mar 11;210(3):433-43. (PMID: 23440042)
Nat Genet. 2018 Mar;50(3):344-348. (PMID: 29483653)
Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2788-93. (PMID: 16477002)
Nat Rev Genet. 2016 Jan;17(1):19-32. (PMID: 26593421)
Science. 2005 Jun 3;308(5727):1477-80. (PMID: 15933202)
Genet Med. 2004 Jan-Feb;6(1):16-26. (PMID: 14726805)
فهرسة مساهمة: Keywords: IL-21R; IL-2R; SCID; immunodeficiency; splicing
المشرفين على المادة: 0 (IL21R protein, human)
0 (Interleukin-21 Receptor alpha Subunit)
تواريخ الأحداث: Date Created: 20190324 Date Completed: 20200520 Latest Revision: 20200520
رمز التحديث: 20231215
DOI: 10.1007/s10875-019-00606-7
PMID: 30903457
قاعدة البيانات: MEDLINE
الوصف
تدمد:1573-2592
DOI:10.1007/s10875-019-00606-7