RESUMO
Omenn syndrome (OS) is a type of severe combined immunodeficiency (SCID) that is distinguished by, lymphadenopathy, hepatosplenomegaly, erythroderma, alopecia with normal to elevated T-cell counts, eosinophilia, and elevated serum IgE levels. Recombination activation gene (RAG) 1 or RAG2 mutations that result in partial V(D)J recombination activity are known to be the main cause of OS. Other genes (DCLRE1C, LIG4, IL7RA, common gamma chain, ADA, RMRP, and CHD7) have also been linked to OS, although with low frequency. Here, we report a two-month-old Moroccan girl from consanguineous marriage with chronic diarrhea, recurrent and opportunistic infections, failure to thrive, desquamative erythroderma, hepatosplenomegaly, and axillary lymphadenitis. The immunological assessment showed normal lymphocyte and NK cell counts but an absence of B cells, agammaglobulinemia contrasting with a high level of IgE. On the other hand, Sanger sequencing of RAG1 and RAG2 exon 2 regions revealed a new homozygous deleterious mutation in the RAG1 gene. This c.1184C > T mutation caused a change from Proline to Leucine at position 395 of the protein, leading to a partial loss of function. Early and rapid diagnosis of the disease may facilitate urgent life-saving treatment.
Assuntos
Genes RAG-1 , Predisposição Genética para Doença , Homozigoto , Mutação , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Alelos , Substituição de Aminoácidos , Feminino , Estudos de Associação Genética , Humanos , Lactente , Fenótipo , Análise de Sequência de DNARESUMO
Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency (PID), characterized by fatal opportunistic infections. The ADA gene encodes adenosine deaminase, an enzyme that catalyzes the irreversible deamination of adenosine and deoxyadenosine in the catabolic pathway of purine. Mutations of the ADA gene have been identified in patients with severe combined immunodeficiency. In this study, we performed a bioinformatics analysis of the human ADA gene to identify potentially harmful nonsynonymous SNPs and their effect on protein structure and stability. Using eleven prediction tools, we identified 15 nsSNPs (H15D, H15P, H17Q, H17Y, D19N, T26I, G140E, C153F, A183D, G216R, H258Y, C262Y, S291L, S291W, and K34OE) as harmful. The results of ConSurf's analysis revealed that all these nsSNPs are localised in the highly conserved positions and affect the structure of the native proteins. In addition, our computational analysis showed that the H15D, G140E, G216R, and S291L mutations identified as being associated with severe combined immunodeficiency affect protein structure. Similarly, the results of the analyses of Rmsd, Rmsf, and Rg showed that all these factors influence protein stability, flexibility, and compaction with different levels of impact. This study is the first comprehensive computational analysis of nsSNPs of the ADA gene. However, functional analyses are needed to elucidate the biological mechanisms of these polymorphisms in severe combined immunodeficiency.
Assuntos
Adenosina Desaminase/química , Adenosina Desaminase/genética , Modelos Moleculares , Polimorfismo de Nucleotídeo Único , Imunodeficiência Combinada Severa/genética , Sequência de Aminoácidos , Sequência de Bases , Sequência Conservada , Dano ao DNA , Humanos , Simulação de Dinâmica Molecular , Mutação , Conformação Proteica , Estabilidade Proteica , Relação Estrutura-AtividadeRESUMO
BACKGROUND: The recombination-activating gene 1 and 2 (RAG1/RAG2) proteins are essential to initiate the V(D)J recombination process, the result is a diverse repertoire of antigen receptor genes and the establishment of the adaptive immunity. RAG1 mutations can lead to multiple forms of combined immunodeficiency. METHODS: In this report, whole exome sequencing was performed in a Moroccan child suffering from combined immunodeficiency, with T and B lymphopenia, autoimmune hemolytic anemia, and cytomegalovirus (CMV) infection. RESULTS: After filtering data and Sanger sequencing validation, one homozygous mutation c.2446G>A (p.Gly816Arg) was identified in the RAG1 gene. CONCLUSION: This finding expands the spectrum of immunological and genetic profiles linked to RAG1 mutation, it also illustrates the necessity to consider RAG1 immunodeficiency in the presence of autoimmune hemolytic anemia and CMV infection, even assuming the immunological phenotype appears more or less normal.
