title: Compound heterozygous mutation of Rag1 leading to Omenn syndrome.
abstract: Omenn syndrome is a primary immunodeficiency disorder, featuring susceptibility to infections and autoreactive T cells and resulting from defective genomic rearrangement of genes for the T cell and B cell receptors. The most frequent etiologies are hypomorphic mutations in "non-core" regions of the Rag1 or Rag2 genes, the protein products of which are critical members of the cellular apparatus for V(D)J recombination. In this report, we describe an infant with Omenn syndrome with a previously unreported termination mutation (p.R142*) in Rag1 on one allele and a partially characterized substitution mutation (p.V779M) in a "core" region of the other Rag1 allele. Using a cellular recombination assay, we found that while the p.R142* mutation completely abolished V(D)J recombination activity, the p.V779M mutation conferred a severe, but not total, loss of V(D)J recombination activity. The recombination defect of the V779 mutant was not due to overall misfolding of Rag1, however, as this mutant supported wild-type levels of V(D)J cleavage. These findings provide insight into the role of this poorly understood region of Rag1 and support the role of Rag1 in a post-cleavage stage of recombination.
authors: Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, MA 02114, United States of America; Department of Biological Sciences, Wellesley College, 106 Central St., Wellesley, MA, 02481, United States of America.
authors: Adam G W
authors: AG
authors: Matthews
authors: Molecular Genetics Core Facility, Children's Hospital Boston, Boston, MA 02115, United States of America.
authors: Christine E
authors: CE
authors: Briggs
authors: Department of Dermatology, Mie University, Graduate School of Medicine, Mie 514-8507, Japan.
authors: Keiichi
authors: K
authors: Yamanaka
authors: Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, United States of America.
authors: Trudy N
authors: TN
authors: Small
authors: Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Boston Children's Hospital, Boston, MA 02115, United States of America.
authors: Jana L
authors: JL
authors: Mooster
authors: Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Boston Children's Hospital, Boston, MA 02115, United States of America.
authors: Francisco A
authors: FA
authors: Bonilla
authors: Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, MA 02114, United States of America.
authors: Marjorie A
authors: MA
authors: Oettinger
authors: Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, United States of America.
authors: Manish J
authors: MJ
authors: Butte
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense; D059748:Proteolysis; D011995:Recombination, Genetic; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C064658:RAG-1 protein