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Publication : The Common R71H-G230A-R293Q Human TMEM173 Is a Null Allele.

First Author  Patel S Year  2017
Journal  J Immunol Volume  198
Issue  2 Pages  776-787
PubMed ID  27927967 Mgi Jnum  J:247744
Mgi Id  MGI:5927347 Doi  10.4049/jimmunol.1601585
Citation  Patel S, et al. (2017) The Common R71H-G230A-R293Q Human TMEM173 Is a Null Allele. J Immunol 198(2):776-787
abstractText  TMEM173 encodes MPYS/STING and is an innate immune sensor for cyclic dinucleotides (CDNs) playing a critical role in infection, inflammation, and cancer. The R71H-G230A-R293Q (HAQ) of TMEM173 is the second most common human TMEM173 allele. In this study, using data from the 1000 Genomes Project we found that homozygous HAQ individuals account for approximately 16.1% of East Asians and approximately 2.8% of Europeans whereas Africans have no homozygous HAQ individuals. Using B cells from homozygous HAQ carriers, we found, surprisingly, that HAQ/HAQ carriers express extremely low MPYS protein and have a decreased TMEM173 transcript. Consequently, the HAQ/HAQ B cells do not respond to CDNs. We subsequently generated an HAQ knock-in mouse expressing a mouse equivalent of the HAQ allele (mHAQ). The mHAQ mouse has decreased MPYS protein in B cells, T cells, Ly6Chi monocytes, bone marrow-derived dendritic cells, and lung tissue. The mHAQ mouse also does not respond to CDNs in vitro and in vivo. Lastly, Pneumovax 23, with an efficacy that depends on TMEM173, is less effective in mHAQ mice than in wild type mice. We conclude that HAQ is a null TMEM173 allele. Our findings have a significant impact on research related to MPYS-mediated human diseases and medicine.
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