Lack of nonfunctional B-cell receptor rearrangements in a patient with normal B cell numbers despite partial RAG1 deficiency and atypical SCID/Omenn syndrome.
BACKGROUND
A 2.5-month old boy presented with recurrent wheezing, protracted diarrhea, erythrodermia, and failure to thrive.


RESULTS
Laboratory analysis showed lymphocytopenia with severely reduced T-cell numbers but normal numbers of B and NK cells. Serum IgE was increased and the patient had eosinophilia. These presentations are consistent with atypical severe combined immunodeficiency (SCID)/Omenn Syndrome and the diagnosis was confirmed by demonstration of homozygosity for the R841W mutation in the catalytic core of RAG1. Comparison of the patient's immunoglobulin heavy chain rearrangements to those of age-matched controls, cord blood, and adults revealed an almost total lack of nonproductive rearrangements (2.7% versus 14.7%, 27.6%, and 19.8% in the controls, respectively) indicating failure to correct out-of-frame rearrangements by a second rearrangement on the homologous chromosome 14.


CONCLUSIONS
We hypothesize that the R841W mutation causes a malfunction of RAG1 that has differential outcome on V(D)J recombination in B and T cells, as the patient had normal B cell numbers but suffered severe alpha-beta T-cell immunodeficiency.
Ohm-Laursen
Line
L
Department of Clinical Immunology, Odense University Hospital, 5000 Odense, Denmark.
Nielsen
Christian
C
Fisker
Niels
N
Lillevang
Søren Thue
ST
Barington
Torben
T
D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology*; D002883:Chromosomes, Human, Pair 14; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007223:Infant; D008231:Lymphopenia / Q000276:immunology; D008297:Male; D009154:Mutation / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency* / Q000235:genetics; D012135:Respiratory Sounds / Q000276:immunology; D016511:Severe Combined Immunodeficiency / Q000097:blood / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
D018398:Homeodomain Proteins; D011947:Receptors, Antigen, B-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; C064658:RAG-1 protein; D007073:Immunoglobulin E