Harjit Dadi1, Tyler A Jones2, Daniele Merico3, Nigel Sharfe1, Adi Ovadia1, Yael Schejter1, Brenda Reid1, Mark Sun3, Linda Vong1, Adelle Atkinson4, Sasson Lavi4, Joel L Pomerantz2, Chaim M Roifman5. 1. Division of Immunology and Allergy, Department of Pediatrics, Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada; Canadian Centre for Primary Immunodeficiency and the Jeffrey Modell Research Laboratory for the Diagnosis of Primary Immunodeficiency, Hospital for Sick Children, Toronto, Ontario, Canada. 2. Department of Biological Chemistry and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Md. 3. Deep Genomics, Toronto, Ontario, Canada. 4. Division of Immunology and Allergy, Department of Pediatrics, Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada. 5. Division of Immunology and Allergy, Department of Pediatrics, Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada; Canadian Centre for Primary Immunodeficiency and the Jeffrey Modell Research Laboratory for the Diagnosis of Primary Immunodeficiency, Hospital for Sick Children, Toronto, Ontario, Canada. Electronic address: chaim.roifman@sickkids.ca.
Abstract
BACKGROUND: Combined immunodeficiency (CID) is a T-cell defect frequently presenting with recurrent infections, as well as associated immune dysregulation manifesting as autoimmunity or allergic inflammation. OBJECTIVE: We sought to identify the genetic aberration in 4 related patients with CID, early-onset asthma, eczema, and food allergies, as well as autoimmunity. METHODS: We performed whole-exome sequencing, followed by Sanger confirmation, assessment of the genetic variant effect on cell signaling, and evaluation of the resultant immune function. RESULTS: A heterozygous novel c.C88T 1-bp substitution resulting in amino acid change R30W in caspase activation and recruitment domain family member 11 (CARD11) was identified by using whole-exome sequencing and segregated perfectly to family members with severe atopy only but was not found in healthy subjects. We demonstrate that the R30W mutation results in loss of function while also exerting a dominant negative effect on wild-type CARD11. The CARD11 defect altered the classical nuclear factor κB pathway, resulting in poor in vitro T-cell responses to mitogens and antigens caused by reduced secretion of IFN-γ and IL-2. CONCLUSION: Unlike patients with biallelic mutations in CARD11 causing severe CID, the R30W defect results in a less profound yet prominent susceptibility to infections, as well as multiorgan atopy and autoimmunity.
BACKGROUND:Combined immunodeficiency (CID) is a T-cell defect frequently presenting with recurrent infections, as well as associated immune dysregulation manifesting as autoimmunity or allergic inflammation. OBJECTIVE: We sought to identify the genetic aberration in 4 related patients with CID, early-onset asthma, eczema, and food allergies, as well as autoimmunity. METHODS: We performed whole-exome sequencing, followed by Sanger confirmation, assessment of the genetic variant effect on cell signaling, and evaluation of the resultant immune function. RESULTS: A heterozygous novel c.C88T 1-bp substitution resulting in amino acid change R30W in caspase activation and recruitment domain family member 11 (CARD11) was identified by using whole-exome sequencing and segregated perfectly to family members with severe atopy only but was not found in healthy subjects. We demonstrate that the R30W mutation results in loss of function while also exerting a dominant negative effect on wild-type CARD11. The CARD11 defect altered the classical nuclear factor κB pathway, resulting in poor in vitro T-cell responses to mitogens and antigens caused by reduced secretion of IFN-γ and IL-2. CONCLUSION: Unlike patients with biallelic mutations in CARD11 causing severe CID, the R30W defect results in a less profound yet prominent susceptibility to infections, as well as multiorgan atopy and autoimmunity.
Authors: Shirly Frizinsky; Erez Rechavi; Ortal Barel; Rose H Najeeb; Shoshana Greenberger; Yu Nee Lee; Amos J Simon; Atar Lev; Chi A Ma; Guangping Sun; Sarah A Blackstone; Joshua D Milner; Raz Somech; Tali Stauber Journal: J Clin Immunol Date: 2019-04-29 Impact factor: 8.317
Authors: Zhaoquan Wang; Shelby M Hutcherson; Chao Yang; Rakhi P Jattani; Julia M Tritapoe; Yong-Kang Yang; Joel L Pomerantz Journal: J Biol Chem Date: 2019-08-07 Impact factor: 5.157
Authors: Batsukh Dorjbal; Jeffrey R Stinson; Chi A Ma; Michael A Weinreich; Bahar Miraghazadeh; Julia M Hartberger; Stefanie Frey-Jakobs; Stephan Weidinger; Lena Moebus; Andre Franke; Alejandro A Schäffer; Alla Bulashevska; Sebastian Fuchs; Stephan Ehl; Sandhya Limaye; Peter D Arkwright; Tracy A Briggs; Claire Langley; Claire Bethune; Andrew F Whyte; Hana Alachkar; Sergey Nejentsev; Thomas DiMaggio; Celeste G Nelson; Kelly D Stone; Martha Nason; Erica H Brittain; Andrew J Oler; Daniel P Veltri; T Ronan Leahy; Niall Conlon; Maria C Poli; Arturo Borzutzky; Jeffrey I Cohen; Joie Davis; Michele P Lambert; Neil Romberg; Kathleen E Sullivan; Kenneth Paris; Alexandra F Freeman; Laura Lucas; Shanmuganathan Chandrakasan; Sinisa Savic; Sophie Hambleton; Smita Y Patel; Michael B Jordan; Amy Theos; Jeffrey Lebensburger; T Prescott Atkinson; Troy R Torgerson; Ivan K Chinn; Joshua D Milner; Bodo Grimbacher; Matthew C Cook; Andrew L Snow Journal: J Allergy Clin Immunol Date: 2018-08-28 Impact factor: 10.793