{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T13:36:37Z","timestamp":1787405797778,"version":"build-2736575974"},"reference-count":36,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2020,6,22]],"date-time":"2020-06-22T00:00:00Z","timestamp":1592784000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["314061271\u2010TRR 205"],"award-info":[{"award-number":["314061271\u2010TRR 205"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["KO 3588\/2\u20101"],"award-info":[{"award-number":["KO 3588\/2\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neurogastroenterology Motil"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Achalasia is a condition characterized by impaired function of esophageal motility and incomplete relaxation of the lower esophagus sphincter, causing dysphagia and regurgitation. Rare cases of early\u2010onset achalasia appear often in combination with further symptoms in a syndromic form as an inherited disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole genome sequencing was used to investigate the genetic basis of isolated achalasia in a family of Tunisian origin. We analyzed the function of the affected protein with immunofluorescence and affinity chromatography study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>A homozygous nonsense mutation was detected in murine retrovirus integration site 1 (<jats:italic>MRVI1<\/jats:italic>) gene (Human Genome Organisation Gene Nomenclature Committee (HGNC) approved gene symbol: <jats:italic>IRAG1<\/jats:italic>) encoding the inositol 1,4,5\u2010trisphosphate receptor 1 (IP<jats:sub>3<\/jats:sub>R1)\u2010associated cyclic guanosine monophosphate (cGMP) kinase substrate (IRAG). Sanger sequencing confirmed co\u2010segregation of the mutation with the disease. Sequencing of the entire <jats:italic>MRVI1<\/jats:italic> gene in 35 additional patients with a syndromic form of achalasia did not uncover further cases with <jats:italic>MRVI1<\/jats:italic> mutations. Immunofluorescence analysis of transfected COS7 cells revealed GFP\u2010IRAG with the truncating mutation p.Arg112* (transcript variant 1) or p.Arg121* (transcript variant 2) to be mislocalized in the cytoplasm and the nucleus. Co\u2010transfection with cGMP\u2010dependent protein kinase 1 isoform \u03b2 (cGK1\u03b2) depicted a partial mislocalization of cGK1\u03b2 due to mislocalized truncated IRAG. Isolation of protein complexes revealed that the truncation of this protein causes the loss of the interaction domain of IRAG with cGK1\u03b2.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions &amp; Inferences<\/jats:title><jats:p>In individuals with an early onset of achalasia without further accompanying symptoms, <jats:italic>MRVI1<\/jats:italic> mutations should be considered as the disease\u2010causing defect.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nmo.13923","type":"journal-article","created":{"date-parts":[[2020,6,23]],"date-time":"2020-06-23T02:57:16Z","timestamp":1592881036000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Homozygous mutation in <i>murine retrovirus integration site 1<\/i> gene associated with a non\u2010syndromic form of isolated familial achalasia"],"prefix":"10.1111","volume":"32","author":[{"given":"Katrin","family":"Koehler","sequence":"first","affiliation":[{"name":"Medizinische Fakult\u00e4t Carl Gustav Carus Children\u2019s Hospital Technische Universit\u00e4t Dresden Dresden Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorra","family":"Hmida","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Anatomy and Cytology Farhat Hached Hospital Sousse Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Schlossmann","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Institute of Pharmacy University of Regensburg Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana","family":"Landgraf","sequence":"additional","affiliation":[{"name":"Medizinische Fakult\u00e4t Carl Gustav Carus Children\u2019s Hospital Technische Universit\u00e4t Dresden Dresden Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Reisch","sequence":"additional","affiliation":[{"name":"Medizinische Klinik und Poliklinik IV Ludwig\u2010Maximilians\u2010Universit\u00e4t M\u00fcnchen Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Schuelke","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics and NeuroCure Clinical Research Center Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Huebner","sequence":"additional","affiliation":[{"name":"Medizinische Fakult\u00e4t Carl Gustav Carus Children\u2019s Hospital Technische Universit\u00e4t Dresden Dresden Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,6,22]]},"reference":[{"key":"e_1_2_9_2_1","first-page":"411","article-title":"An overview of 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