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Cardiovascular complications dominate its clinical presentation, but gastrointestinal (GI) dysfunction significantly affects quality of life. To investigate the structural, functional, and cellular basis of gut dysmotility in MSMDS, we reviewed clinical data from 24 patients with MSMDS and studied the ACTA2 R179H mouse model. Patients exhibited severe gut dysmotility, with 75% requiring medication for chronic constipation. ACTA2 mutant mice displayed cecal and colonic dilatation, reduced intestinal length, and disrupted colonic migrating motor complexes. Delayed whole-gut transit and impaired contractile responses to electrical and pharmacological stimulation were observed. Transcriptomic analysis revealed significant actin cytoskeleton-related gene changes in smooth muscle cells, and immune profiling identified increased lymphocytic infiltration. Despite functional abnormalities, there were no obvious changes in the enteric nervous system. These findings establish ACTA2 mice as a robust model for studying GI pathology in MSMDS, elucidating the role of smooth muscle dysfunction in gut dysmotility. This model provides a foundation for developing targeted therapies aimed at restoring intestinal motility by directly addressing actin cytoskeletal disruptions in smooth muscle cells.<\/jats:p>","DOI":"10.1172\/jci.insight.190469","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T17:00:26Z","timestamp":1767718826000},"source":"Crossref","is-referenced-by-count":0,"title":["Structural and functional gastrointestinal abnormalities in ACTA2 R179H mice modeling multisystemic smooth muscle dysfunction syndrome"],"prefix":"10.1172","volume":"11","author":[{"given":"Ahmed A.","family":"Rahman","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rhian","family":"Stavely","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leah C.","family":"Ott","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher Y.","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kensuke","family":"Ohishi","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd., Akitakata, Hiroshima, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryo","family":"Hotta","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan J.","family":"Burns","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabyasachi","family":"Das","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Da Cruz","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA."},{"name":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Tambala","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA."},{"name":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark E.","family":"Lindsay","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Program;"},{"name":"Cardiovascular Research Center, Division of Cardiology, Department of Medicine; 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