These two authors contributed equally to this work.
Dominant-negative STAT1 SH2 domain mutations in unrelated patients with mendelian susceptibility to mycobacterial disease†
Article first published online: 7 JUN 2012
© 2012 Wiley Periodicals, Inc.
Special Issue: Databases in Neurogenetics
Volume 33, Issue 9, pages 1377–1387, September 2012
How to Cite
Tsumura, M., Okada, S., Sakai, H., Yasunaga, S., Ohtsubo, M., Murata, T., Obata, H., Yasumi, T., Kong, X.-F., Abhyankar, A., Heike, T., Nakahata, T., Nishikomori, R., Al-Muhsen, S., Boisson-Dupuis, S., Casanova, J.-L., AlZahrani, M., Shehri, M. A., ElGhazali, G., Takihara, Y. and Kobayashi, M. (2012), Dominant-negative STAT1 SH2 domain mutations in unrelated patients with mendelian susceptibility to mycobacterial disease. Hum. Mutat., 33: 1377–1387. doi: 10.1002/humu.22113
Communicated by Jacques S. Beckmann
- Issue published online: 13 AUG 2012
- Article first published online: 7 JUN 2012
- Accepted manuscript online: 9 MAY 2012 03:54PM EST
- Manuscript Accepted: 30 APR 2012
- Manuscript Received: 13 FEB 2012
- Grants in Aid for Scientific Research from the Japan Society for the Promotion of Science (20790731 to S.O); Grants-in Aid for Scientific Research from the Ministry of Education, Culture, Sport, Science and Technology of Japan (22591161 to M.K.); Research on Measures for Intractable Diseases funding from the Japanese Ministry of Health, Labor and Welfare (H22-Nanchi-ippan-078 to M.K.); grants from the Bill and Melinda Gates Foundation, the St. Giles Foundation, the Jeffrey Modell Foundation and Talecris Biotherapeutics, the Rockefeller University Center for Clinical and Translational Science (5UL1RR024143-03), the Rockefeller University, and the National Institute of Allergy and Infectious Diseases (1R01AI089970-01) supported the Laboratory of Human Genetics of Infectious Diseases; Analysis Center of Life Science, Hiroshima University supported Sequence analysis.
- dominant-negative effect
Patients carrying two loss-of-function (or hypomorphic) alleles of STAT1 are vulnerable to intracellular bacterial and viral diseases. Heterozygosity for loss-of-function dominant-negative mutations in STAT1 is responsible for autosomal dominant (AD) Mendelian susceptibility to mycobacterial disease (MSMD), whereas heterozygosity for gain-of-function loss-of-dephosphorylation mutations causes AD chronic mucocutaneous candidiasis (CMC). The two previously reported types of AD MSMD-causing STAT1 mutations are located in the tail segment domain (p.L706S) or in the DNA-binding domain (p.E320Q and p.Q463H), whereas the AD CMC-causing mutations are located in the coiled-coil domain. We identified two cases with AD-STAT1 deficiency in two unrelated patients from Japan and Saudi Arabia carrying heterozygous missense mutations affecting the SH2 domain (p.K637E and p.K673R). p.K673R is a hypomorphic mutation that impairs STAT1 tyrosine phosphorylation, whereas the p.K637E mutation is null and affects both STAT1 phosphorylation and DNA-binding activity. Both alleles are dominant negative and result in impaired STAT1-mediated cellular responses to interferon (IFN)-γ and IL-27. In contrast, STAT1-mediated cellular responses against IFN-α and IFN-λ1 were preserved at normal levels in patients' cells. We describe here the first dominant mutations in the SH2 domain of STAT1, revealing the importance of this domain for tyrosine phosphorylation and DNA binding, as well as for antimycobacterial immunity. Hum Mutat 33:1377–1387, 2012. © 2012 Wiley Periodicals, Inc.