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title alternative
多発性骨髄炎母子例で同定したSTAT1新規ヘテロ接合性遺伝子変異Y701Cとその機能解析
creator
Hirata, Osamu
NDC
Medical sciences
abstract
Heterozygosity for dominant-negative STAT1 mutations underlies autosomal dominant Mendelian susceptibility to mycobacterial diseases. Mutations conferring Mendelian susceptibility to mycobacterial diseases have been identified in the regions of the STAT1 gene encoding the tail segment, DNA-binding domain and SH2 domain. We describe here a new heterozygous mutation, Y701C, in a Japanese two-generation multiplex kindred with autosomal dominant Mendelian susceptibility to mycobacterial diseases. This mutation affects precisely the canonical STAT1 tyrosine phosphorylation site. The Y701C STAT1 protein is produced normally, but its phosphorylation is abolished, resulting in a loss-of-function for STAT1-dependent cellular responses to IFN-γ or IFN-α. In the patient's cells, the allele is dominant-negative for gamma-activated factor-mediated responses to IFN-γ, but not for IFN-stimulated gene factor-3-mediated responses to IFN-α/β, accounting for the clinical phenotype of Mendelian susceptibility to mycobacterial diseases without severe viral diseases. Interestingly, both patients displayed multifocal osteomyelitis, which is often seen in Mendelian susceptibility to mycobacterial diseases patients with autosomal dominant partial IFN-γR1 deficiency. Multifocal osteomyelitis should thus prompt investigations of both STAT1 and IFN-γR1. This experiment of Nature also confirms the essential role of tyrosine 701 in human STAT1 activity in natura.
description
This study was supported, in part, by Grants in Aid for Scientific Research from the Japan Society for the Promotion of Science [22591161 to M.K.], and by Research on Measures for Intractable Diseases funding from the Japanese Ministry of Health, Labor and Welfare [H22-Nanchi-ippan-078 to M.K.]. This study was also supported, in part, by the Rockefeller University and grants from the National Center for Research Resources, and the National Center for Advancing Sciences (NCATS), National Institutes of Health (NIH) grant number 8UL1TR000043, NIH grant number R01AI089970, and the St. Giles Foundation. S.C. was supported by the AXA Research Fund and X-F.K. by the Stony Wold-Herbert Fund.
date of created
2014-11-21
language
eng
nii type
Thesis or Dissertation
HU type
Doctoral Theses
DCMI type
text
format
application/pdf
text version
ETD
rights
Copyright(c) by Author
relation references
Osamu Hirata, Satoshi Okada, Miyuki Tsumura, Reiko Kagawa, Mizuka Miki, Hiroshi Kawaguchi, Kazuhiro Nakamura, Stephanie Boisson-Dupuis, Jean-Laurent Casanova, Yoshihiro Takihara and Masao Kobayashi; Heterozygosity for the Y701C STAT1 mutation in a multiplex kindred with multifocal osteomyelitis; Haematologica The Hematology Journal, October 2013 98: 1641-1649 (doi: 10.3324/haematol.2013.083741)
relation references URL
http://dx.doi.org/10.3324/haematol.2013.083741
grantid
甲第6198号
degreeGrantor
広島大学(Hiroshima University)
degreename Ja
博士(医学)
degreename En
Philosophy in Medical Science
degreelevel
doctoral
date of granted
2013-05-23
department
Graduate School of Biomedical Science