Homozygous deletion of RAG1, RAG2 and 5' region TRAF6 causes severe immune suppression and atypical osteopetrosis.
Mutations of several genes have been implicated in autosomal recessive osteopetrosis (OP), a disease caused by impaired function and differentiation of osteoclasts. Severe combined immune deficiencies (SCID) can likewise result from different genetic mutations. We report two siblings with SCID and an atypical phenotype of OP. A biallelic microdeletion encompassing the 5' region of TRAF6, RAG1 and RAG2 genes was identified. TRAF6, a tumor necrosis factor receptor-associated family member, plays an important role in T cell signaling and in RANKL-dependent osteoclast differentiation and activation but its role in human OP has not been previously reported. The RAG proteins are essential for recombination of B and T cell receptors, and for the survival and differentiation of these cells. This is the first study to report a homozygous deletion of TRAF6 as a cause of human disease.
Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.|Raphael Recanati Genetic Institute, Rabin Medical Center, Petach Tikva, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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Weisz Hubshman
Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.|Raphael Recanati Genetic Institute, Rabin Medical Center, Petach Tikva, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Felsenstein Medical Research Center, Petach Tikva, Israel.
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Basel-Vanagaite
Bone Marrow Transplantation Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
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Krauss
Radiology Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
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Konen
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Kipper Institute of Immunology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
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Levy
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Felsenstein Medical Research Center, Petach Tikva, Israel.|Kipper Institute of Immunology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
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Garty
Felsenstein Medical Research Center, Petach Tikva, Israel.|Genomic Bioinformatics Laboratory, Department of Molecular Biology, Ariel University, Ariel, Israel.
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Smirin-Yosef
Raphael Recanati Genetic Institute, Rabin Medical Center, Petach Tikva, Israel.
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Maya
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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Lagovsky
Raphael Recanati Genetic Institute, Rabin Medical Center, Petach Tikva, Israel.
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Taub
Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.|Raphael Recanati Genetic Institute, Rabin Medical Center, Petach Tikva, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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Marom
Hemato-Oncology Department, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
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Gaash
Hemato-Oncology Department, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
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Shichrur
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Felsenstein Medical Research Center, Petach Tikva, Israel.|Hemato-Oncology Department, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
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Avigad
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Pathology Department, Rabin Medical Center, Petach Tikva, Israel.
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Hayman-Manzur
CNR/IRGB, UOS Milan Unit, Milan, Italy.|Humanitas Clinical and Research Center, Milan, Italy.
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Villa
CNR/IRGB, UOS Milan Unit, Milan, Italy.|Humanitas Clinical and Research Center, Milan, Italy.
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Sobacchi
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Bioinformatics Unit, Cancer Center, Sheba Medical Center, Tel Aviv, Israel.|Genetic Institute, Maccabi Megalab, Rehovot, Israel.
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Shohat
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Bone Marrow Transplantation Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
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Yaniv
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Bone Marrow Transplantation Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
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Stein
D020121:5' Untranslated Regions / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010010:Osteoclasts / Q000378:metabolism; D010022:Osteopetrosis / Q000235:genetics* / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics*
D020121:5' Untranslated Regions; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C499311:RAG2 protein, human; D011948:Receptors, Antigen, T-Cell; D048029:TNF Receptor-Associated Factor 6; C000604754:Tifab protein, human; C064658:RAG-1 protein
RAG; SCID; TRAF6; osteopetrosis