PMID- 18768869
OWN - NLM
STAT- MEDLINE
DCOM- 20081118
LR  - 20211020
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 181
IP  - 6
DP  - 2008 Sep 15
TI  - A RAG1 mutation found in Omenn syndrome causes coding flank hypersensitivity: a 
      novel mechanism for antigen receptor repertoire restriction.
PG  - 4124-30
AB  - 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 RAG1 R972Q, corresponding to 
      an OS mutation, renders the recombinase hypersensitive to selected coding 
      sequences at the hairpin formation step. Other RAG1 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.
FAU - Wong, Serre-Yu
AU  - Wong SY
AD  - Program in Molecular Pathogenesis, Helen L. and Martin S. Kimmel Center for 
      Biology and Medicine at the Skirball Institute for Biomolecular Medicine, and 
      Department of Pathology, New York University School of Medicine, New York, NY 
      10016, USA.
FAU - Lu, Catherine P
AU  - Lu CP
FAU - Roth, David B
AU  - Roth DB
LA  - eng
GR  - R01 AI036420/AI/NIAID NIH HHS/United States
GR  - R01 AI036420-15/AI/NIAID NIH HHS/United States
GR  - AI36420/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Homeodomain Proteins)
RN  - 0RH81L854J (Glutamine)
RN  - 128559-51-3 (RAG-1 protein)
RN  - 94ZLA3W45F (Arginine)
RN  - EC 2.7.7.- (VDJ Recombinases)
SB  - IM
MH  - Amino Acid Motifs/genetics
MH  - Amino Acid Substitution/genetics/immunology
MH  - Animals
MH  - Arginine/genetics
MH  - CHO Cells
MH  - Catalytic Domain/genetics
MH  - Cricetinae
MH  - Cricetulus
MH  - Gene Rearrangement, beta-Chain T-Cell Antigen Receptor
MH  - Genes, T-Cell Receptor beta/genetics
MH  - Glutamine/genetics
MH  - Homeodomain Proteins/*genetics/physiology
MH  - Humans
MH  - Mice
MH  - Mutagenesis, Site-Directed
MH  - Severe Combined Immunodeficiency/enzymology/*genetics/*immunology
MH  - VDJ Recombinases/genetics/physiology
PMC - PMC2597290
MID - NIHMS60025
EDAT- 2008/09/05 09:00
MHDA- 2008/11/19 09:00
PMCR- 2009/09/15
CRDT- 2008/09/05 09:00
PHST- 2008/09/05 09:00 [pubmed]
PHST- 2008/11/19 09:00 [medline]
PHST- 2008/09/05 09:00 [entrez]
PHST- 2009/09/15 00:00 [pmc-release]
AID - 181/6/4124 [pii]
AID - 10.4049/jimmunol.181.6.4124 [doi]
PST - ppublish
SO  - J Immunol. 2008 Sep 15;181(6):4124-30. doi: 10.4049/jimmunol.181.6.4124.