Similar recombination-activating gene (RAG) mutations result in similar immunobiological effects but in different clinical phenotypes.

[omenn syndrome]

V (D )J recombination takes place during lymphocyte development to generate a large repertoire of T - and B-cell receptors . Mutations in recombination-activating gene 1 (RAG 1 ) and RAG 2 result in loss or reduction of V (D )J recombination . It is known that different mutations in RAG genes vary in residual recombinase activity and give rise to a broad spectrum of clinical phenotypes .We sought to study the immunologic mechanisms causing the clinical spectrum of RAG deficiency .We included 22 patients with similar RAG 1 mutations (c .519 delT or c .368 _369 delAA ) resulting in N-terminal truncated RAG 1 protein with residual recombination activity but presenting with different clinical phenotypes . We studied precursor B-cell development , immunoglobulin and T -cell receptor repertoire formation , receptor editing , and B- and T -cell numbers .Clinically , patients were divided into 3 main categories : T (-)B (-) severe combined immunodeficiency , Omenn syndrome , and combined immunodeficiency . All patients showed a block in the precursor B-cell development , low B- and T -cell numbers , normal immunoglobulin gene use , limited B- and T -cell repertoires , and slightly impaired receptor editing .This study demonstrates that similar RAG mutations can result in similar immunobiological effects but different clinical phenotypes , indicating that the level of residual recombinase activity is not the only determinant for clinical outcome . We postulate a model in which the type and moment of antigenic pressure affect the clinical phenotypes of these patients .

Diseases
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Diseases presenting "different clinical phenotypes" symptom

allergic bronchopulmonary aspergillosis

classical phenylketonuria

epidermolysis bullosa simplex

omenn syndrome

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