N-terminal RAG1 frameshift mutations in Omenn's syndrome: Internal methionine usage leads to partial V(D)J recombination activity and reveals a fundamental role in vivo for the N-terminal domains

Citation
S. Santagata et al., N-terminal RAG1 frameshift mutations in Omenn's syndrome: Internal methionine usage leads to partial V(D)J recombination activity and reveals a fundamental role in vivo for the N-terminal domains, P NAS US, 97(26), 2000, pp. 14572-14577
Citations number
41
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN journal
0027-8424 → ACNP
Volume
97
Issue
26
Year of publication
2000
Pages
14572 - 14577
Database
ISI
SICI code
0027-8424(200012)97:26<14572:NRFMIO>2.0.ZU;2-J
Abstract
Omenn's syndrome is an autosomal recessive primary immunodeficiency charact erized by variable numbers of T lymphocytes of limited clonality, hypereosi nophilia, and high IgE levels with a paradoxical absence of circulating B l ymphocytes. We have previously attributed this disorder to missense mutatio ns that render the RAG1/RAG2 recombinase only partially active. Here we rep ort seven Omenn's patients with a novel class of genetic lesions: frameshif t mutations within the 5' coding region of RAG1. Interestingly, we demonstr ate in transient expression experiments that these frameshift deletion alle les remain partially functional for both deletional and inversional recombi nation and can hence explain the partial rearrangement phenotype observed i n these patients. The rearrangement activity is mediated by truncated RAG1 proteins that are generated by alternative ATG usage 3' to the frameshift d eletion and that demonstrate improper cellular localization. Taken together , our results suggest a novel mechanism for the development of immunodefici ency in a subset of Omenn's syndrome patients.