{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T15:39:02Z","timestamp":1775576342322,"version":"3.50.1"},"reference-count":28,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T00:00:00Z","timestamp":1621555200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Laboratory Analysis"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p><jats:italic>QRFPR<\/jats:italic> is a recently identified member of the G protein\u2010coupled receptor and is an orphan receptor for 26Rfa, which plays important role in the regulation of many physiological functions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we employed whole exome sequencing (WES) to examine the patients with intellectual disability (ID) and difficulty in feeding. We performed SIFT and PolyPhen2 predictions for the variants. The structure model was built from scratch by I\u2010TASSER. Here, results derived from a number of cell\u2010based functional assays, including shRNA experiment, intracellular Ca<jats:sup>2+<\/jats:sup> measurement, the expression of PI3\u00a0K\u2010AKT\u2010mTOR, and phosphorylation. The functional effect of <jats:italic>QRFPR<\/jats:italic> variants on PI3K\u2010AKT\u2010mTOR signaling was evaluated in vitro transfection experiments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Result<\/jats:title><jats:p>Here, we identified two <jats:italic>QRFPR<\/jats:italic> variants at c.202\u00a0T&gt;C (p.Y68H) and c.1111C&gt;T (p.R371W) in 2 unrelated individuals. Structural analysis revealed that p.Y68H and p.R371W variants may affect the side chain structure of adjacent amino acids causing reduced binding of QRFPR to 26Rfa. The results show that QRFPR stimulated by 26Rfa leading to the transient rise of intracellular Ca<jats:sup>2+<\/jats:sup>. The <jats:italic>QRFPR<\/jats:italic> variations p.Y68H and p.R371\u00a0W can reduce the mobilization of intracellular Ca<jats:sup>2+<\/jats:sup>. The phosphorylation levels of the PI3K, Akt, and mTOR were significantly up\u2010 or downregulated by QRFPR overexpression or silencing, respectively. The <jats:italic>QRFPR<\/jats:italic> variations inhibited PI3K\u2010AKT\u2010mTOR signaling, resulting in downregulation of p\u2010mTOR.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings suggest that QRFPR acts as important role in neurodevelopment, and the effects of <jats:italic>QRFPR<\/jats:italic> are likely to be mediated by the Ca<jats:sup>2+<\/jats:sup>\u2010dependent PI3K\u2010AKT\u2010mTOR pathways. Importantly, these findings provide a foundation for future elucidation of GPCR\u2010mediated signaling and the physiological implications.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcla.23822","type":"journal-article","created":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T10:42:45Z","timestamp":1621593765000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The variations in human orphan G protein\u2010coupled receptor QRFPR affect PI3K\u2010AKT\u2010mTOR signaling"],"prefix":"10.1002","volume":"35","author":[{"given":"Huanzheng","family":"Li","sequence":"first","affiliation":[{"name":"Wenzhou Key Laboratory of Birth Defects Wenzhou Central Hospital Dingli Clinical Medical College of Wenzhou Medical University Wenzhou China"},{"name":"Human Aging Research Institute Nanchang University Nanchang 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Medical University Wenzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunzhi","family":"Xu","sequence":"additional","affiliation":[{"name":"Wenzhou Key Laboratory of Birth Defects Wenzhou Central Hospital Dingli Clinical Medical College of Wenzhou Medical University Wenzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Blood Transfusion The Second Affiliated Hospital of Soochow University Suzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanbao","family":"Xiang","sequence":"additional","affiliation":[{"name":"Wenzhou Key Laboratory of Birth Defects Wenzhou Central Hospital Dingli Clinical Medical College of Wenzhou Medical University Wenzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuan","family":"Lin","sequence":"additional","affiliation":[{"name":"Wenzhou Key Laboratory of Birth Defects Wenzhou 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