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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
immunology and microbiology
A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency
Journal of Allergy and Clinical Immunology, Volume 133, No. 4, Year 2014
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Description
Background The recombination-activating gene (RAG) 1/2 proteins play a critical role in the development of T and B cells by initiating the VDJ recombination process that leads to generation of a broad T-cell receptor (TCR) and B-cell receptor repertoire. Pathogenic mutations in the RAG1/2 genes result in various forms of primary immunodeficiency, ranging from T-B - severe combined immune deficiency to delayed-onset disease with granuloma formation, autoimmunity, or both. It is not clear what contributes to such heterogeneity of phenotypes. Objective We sought to investigate the molecular basis for phenotypic diversity presented in patients with various RAG1 mutations. Methods We have developed a flow cytometry-based assay that allows analysis of RAG recombination activity based on green fluorescent protein expression and have assessed the induction of the Ighc locus rearrangements in mouse Rag1-/- pro-B cells reconstituted with wild-type or mutant human RAG1 (hRAG1) using deep sequencing technology. Results Here we demonstrate correlation between defective recombination activity of hRAG1 mutant proteins and severity of the clinical and immunologic phenotype and provide insights on the molecular mechanisms accounting for such phenotypic diversity. Conclusions Using a sensitive assay to measure the RAG1 activity level of 79 mutations in a physiologic setting, we demonstrate correlation between recombination activity of RAG1 mutants and the severity of clinical presentation and show that RAG1 mutants can induce specific abnormalities of the VDJ recombination process. © 2013 American Academy of Allergy, Asthma & Immunology.
Authors & Co-Authors
Lee, Yunee
United States, Boston
Boston Children's Hospital
Frugoni, Francesco
United States, Boston
Boston Children's Hospital
Dobbs, Kerry
United States, Boston
Boston Children's Hospital
Walter, Jolán Eszter
United States, Boston
Boston Children's Hospital
United States, Boston
Massachusetts General Hospital
Giliani, S.
Italy, Brescia
Università Degli Studi Di Brescia
Gennery, Andrew R.
United Kingdom, Newcastle
The Newcastle Upon Tyne Hospitals Nhs Foundation Trust
Al-Herz, Waleed
Kuwait, Kuwait City
Kuwait University
Haddad, Elie
Canada, Montreal
Chu Sainte-justine - le Centre Hospitalier Universitaire Mère-enfant
Ledeist, Francoise
Canada, Montreal
Chu Sainte-justine - le Centre Hospitalier Universitaire Mère-enfant
Bleesing, Jack Jan Hendrik
United States, Cincinnati
Cincinnati Children's Hospital Medical Center
Henderson, Lauren A.
United States, Boston
Boston Children's Hospital
Pai, Sung-yun
United States, Boston
Boston Children's Hospital
Nelson, Robert P.
United States, Indianapolis
Indiana University School of Medicine
El-Ghoneimy, Dalia Helmy
Egypt, Cairo
Ain Shams University Children's Hospital
El Feky, Reem
Egypt, Cairo
Ain Shams University Children's Hospital
Reda, Shereen Medhat
Egypt, Cairo
Ain Shams University Children's Hospital
Hossny, Elham
Egypt, Cairo
Ain Shams University Children's Hospital
Soler-Palacín, P.
Spain, Barcelona
Hospital Universitari Vall D'hebron
Fuleihan, Ramsay L.
United States, Chicago
Northwestern University Feinberg School of Medicine
Patel, Niraj C.
United States, Charlotte
Carolinas Medical Center
Massaad, Michel J.
United States, Boston
Boston Children's Hospital
Geha, Raif S.
United States, Boston
Boston Children's Hospital
Puck, Jennifer M.
United States, San Francisco
Ucsf Benioff Children‘s Hospital
Palma, Paolo
Italy, Rome
Università Degli Studi Di Roma Tor Vergata
Cancrini, Caterina
Italy, Rome
Università Degli Studi Di Roma Tor Vergata
Chen, Karin
United States, Salt Lake City
The University of Utah
Vihinen, Mauno
Sweden, Lund
Institutionen För Experimentell Medicinsk Vetenskap
Alt, Frederick W.
United States, Boston
Boston Children's Hospital
Notarangelo, Luigi Daniele
United States, Boston
Boston Children's Hospital
Statistics
Citations: 125
Authors: 29
Affiliations: 16
Identifiers
Doi:
10.1016/j.jaci.2013.10.007
ISSN:
00916749
e-ISSN:
10976825
Research Areas
Genetics And Genomics
Study Approach
Systematic review