Compound Heterozygous Mutation of Rag1 Leading to Omenn Syndrome
| Autor: | Francisco A. Bonilla, Christine Briggs, Marjorie A. Oettinger, Trudy N. Small, Jana L. Mooster, Keiichi Yamanaka, Manish J. Butte, Adam G. W. Matthews |
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| Přispěvatelé: | Fugmann, Sebastian D |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Heterozygote General Science & Technology Mutant Nonsense mutation Mutation Missense lcsh:Medicine chemical and pharmacologic phenomena Biology Compound heterozygosity Recombination-activating gene Rare Diseases Genetic RAG2 Genetics medicine 2.1 Biological and endogenous factors Missense mutation Humans Aetiology Preschool lcsh:Science Child Alleles Homeodomain Proteins Recombination Genetic Multidisciplinary Point mutation lcsh:R Infant Newborn Infant hemic and immune systems Newborn medicine.disease Molecular biology Recombination Omenn syndrome 3. Good health Amino Acid Substitution Child Preschool Mutation Proteolysis lcsh:Q Severe Combined Immunodeficiency Missense Biotechnology Research Article |
| Zdroj: | PLoS ONE PLoS ONE, Vol 10, Iss 4, p e0121489 (2015) PloS one, vol 10, iss 4 |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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