A RAG1 mutation found in Omenn syndrome causes coding flank hypersensitivity: a novel mechanism for antigen receptor repertoire restriction.

[omenn syndrome]

Hypomorphic RAG mutants with severely reduced V (D )J recombination activity cause Omenn Syndrome (OS ), an immunodeficiency with features of immune dysregulation and a restricted TCR repertoire . Precisely how RAG mutants produce autoimmune and allergic symptoms has been unclear . Current models posit that the severe recombination defect restricts the number of lymphocyte clones , a few of which are selected upon Ag exposure . We show that murine RAG 1 R 972 Q , corresponding to an OS mutation , renders the recombinase hypersensitive to selected coding sequences at the hairpin formation step . Other RAG 1 OS mutants tested do not manifest this sequence sensitivity . These new data support a novel mechanism for OS : by selectively impairing recombination at certain coding flanks , a RAG mutant can cause primary repertoire restriction , as opposed to a more random , limited repertoire that develops secondary to severely diminished recombination activity .

Diseases
Validation

Diseases presenting "immunodeficiency" symptom

adrenal incidentaloma

allergic bronchopulmonary aspergillosis

cushing syndrome

dracunculiasis

hirschsprung disease

hodgkin lymphoma, classical

homocystinuria without methylmalonic aciduria

kabuki syndrome

legionellosis

malignant atrophic papulosis

oculocutaneous albinism

omenn syndrome

papillon-lefèvre syndrome

primary effusion lymphoma

primary hyperoxaluria type 1

pyomyositis

severe combined immunodeficiency

sneddon syndrome

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

This symptom has already been validated