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

Seema Patel1, Steven M Blaauboer2, Heidi R Tucker2

  • 1Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL 32610.

Journal of Immunology (Baltimore, Md. : 1950)
|December 9, 2016
PubMed

Insights

The common TMEM173 R71H-G230A-R293Q (HAQ) allele results in significantly reduced MPYS/STING protein. This HAQ variant acts as a null allele, impairing innate immune responses to cyclic dinucleotides (CDNs).

Area of Science:

  • Immunology
  • Genetics
  • Molecular Biology

Background:

  • TMEM173 encodes MPYS/STING, a crucial innate immune sensor for cyclic dinucleotides (CDNs).
  • The R71H-G230A-R293Q (HAQ) variant of TMEM173 is the second most frequent human allele.
  • Homozygous HAQ allele carriers are prevalent in East Asian and European populations.

Purpose of the Study:

  • To investigate the functional impact of the common TMEM173 HAQ allele on MPYS/STING protein expression and CDN response.
  • To determine the prevalence of homozygous HAQ allele carriers across different ethnic groups.
  • To assess the in vivo consequences of the HAQ allele using a knock-in mouse model.

Main Methods:

  • Analysis of 1000 Genomes Project data to determine HAQ allele frequency.
  • Assessment of MPYS protein and TMEM173 transcript levels in B cells from HAQ carriers.
  • Generation and characterization of a mouse model with the equivalent HAQ allele (mHAQ).
  • In vitro and in vivo evaluation of CDN response in mHAQ mice.
  • Testing the efficacy of Pneumovax 23 in mHAQ mice.

Main Results:

  • Homozygous HAQ allele carriers constitute approximately 16.1% of East Asians and 2.8% of Europeans.
  • HAQ/HAQ carriers exhibit extremely low MPYS protein and decreased TMEM173 transcript levels.
  • HAQ/HAQ B cells and mHAQ mice show a lack of response to cyclic dinucleotides (CDNs).
  • mHAQ mice display reduced MPYS protein across various immune cell types and tissues.
  • Pneumovax 23 efficacy is diminished in mHAQ mice compared to wild-type.

Conclusions:

  • The R71H-G230A-R293Q (HAQ) variant of TMEM173 functions as a null allele.
  • The HAQ allele significantly impairs innate immune sensing of cyclic dinucleotides (CDNs).
  • Findings have substantial implications for understanding MPYS/STING-mediated diseases and developing TMEM173-targeted therapies.

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