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
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
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.