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Koehler, Katrin; Hmida, Dorra; Schlossmann, Jens; Landgraf, Dana; Reisch, Nicole; Schuelke, Markus; Huebner, Angela (2020): Homozygous mutation inmurine retrovirus integration site 1gene associated with a non-syndromic form of isolated familial achalasia. In: Neurogastroenterology and Motility, Vol. 32, No. 12, e13923
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Background: 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-onset achalasia appear often in combination with further symptoms in a syndromic form as an inherited disease. Methods 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. Key Results A homozygous nonsense mutation was detected in murine retrovirus integration site 1 (MRVI1) gene (Human Genome Organisation Gene Nomenclature Committee (HGNC) approved gene symbol:IRAG1) encoding the inositol 1,4,5-trisphosphate receptor 1 (IP(3)R1)-associated cyclic guanosine monophosphate (cGMP) kinase substrate (IRAG). Sanger sequencing confirmed co-segregation of the mutation with the disease. Sequencing of the entireMRVI1gene in 35 additional patients with a syndromic form of achalasia did not uncover further cases withMRVI1mutations. Immunofluorescence analysis of transfected COS7 cells revealed GFP-IRAG 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-transfection with cGMP-dependent protein kinase 1 isoform beta (cGK1 beta) depicted a partial mislocalization of cGK1 beta 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 beta. Conclusions & Inferences: In individuals with an early onset of achalasia without further accompanying symptoms,MRVI1mutations should be considered as the disease-causing defect.