2017
DOI: 10.1073/pnas.1620507114
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Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice

Abstract: Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital visceral myopathy characterized by severe dilation of the urinary bladder and defective intestinal motility. The genetic basis of MMIHS has been ascribed to spontaneous and autosomal dominant mutations in actin gamma 2 (ACTG2), a smooth muscle contractile gene. However, evidence suggesting a recessive origin of the disease also exists. Using combined homozygosity mapping and whole exome sequencing, a genetically isolated family w… Show more

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Cited by 107 publications
(116 citation statements)
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References 61 publications
(73 reference statements)
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“…Patients with mutations in the LMOD1 gene leading to the absence of Lmod1, and a Lmod1À/À mouse model, develop megacystis microcolon intestinal hypoperistalsis syndrome, caused by hypocontractility of bladder and intestinal smooth muscle that leads to functional obstruction of the urinary bladder and intestine (Table 1) (21). MMIHS appears to be a congenital disease due to defective smooth muscle contractility, because sporadic mutations in smooth muscle actin ACTG2 are among the most frequent causes of this syndrome (91), and at least one patient with a nonsense mutation in smooth muscle myosin MYH11 has also been reported (92).…”
Section: Loss Of Lmod2 Leads To Dilated Cardiomyopathy Due To Reducedmentioning
confidence: 99%
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“…Patients with mutations in the LMOD1 gene leading to the absence of Lmod1, and a Lmod1À/À mouse model, develop megacystis microcolon intestinal hypoperistalsis syndrome, caused by hypocontractility of bladder and intestinal smooth muscle that leads to functional obstruction of the urinary bladder and intestine (Table 1) (21). MMIHS appears to be a congenital disease due to defective smooth muscle contractility, because sporadic mutations in smooth muscle actin ACTG2 are among the most frequent causes of this syndrome (91), and at least one patient with a nonsense mutation in smooth muscle myosin MYH11 has also been reported (92).…”
Section: Loss Of Lmod2 Leads To Dilated Cardiomyopathy Due To Reducedmentioning
confidence: 99%
“…MMIHS appears to be a congenital disease due to defective smooth muscle contractility, because sporadic mutations in smooth muscle actin ACTG2 are among the most frequent causes of this syndrome (91), and at least one patient with a nonsense mutation in smooth muscle myosin MYH11 has also been reported (92). Although Lmod1 is abundant in both vascular and visceral smooth muscles (21,(25)(26)(27), Lmod1À/À mice exhibit pathological thinning and compaction of visceral (stomach, bladder, intestine), but surprisingly, not vascular (aorta, esophagus) smooth muscles (21). siRNA knockdown of Lmod1 in isolated intestinal smooth muscle cells results in decreased contractility, indicating that functional defects in vivo are intrinsic to smooth muscle cells.…”
Section: Loss Of Lmod2 Leads To Dilated Cardiomyopathy Due To Reducedmentioning
confidence: 99%
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“…Autosomal recessive forms of MMIHS are caused by biallelic loss‐of‐function variants in other proteins involved in actin–myosin interactions: MYH11 (myosin‐heavy chain; Gauthier et al, ), MYLK (myosin‐light chain kinase; Halim, Brosens, et al, ), LMOD1 (leiomodin 1, an actin‐binding protein expressed primarily in vascular and visceral smooth muscle; Halim, Wilson, et al, ) and MYL9 (regulatory myosin‐light chain; Moreno et al, ). Other genes that are implicated in intestinal hypoperistalsis, but usually with other distinguishing phenotypic features include genes causing mitochondrial disorders ( TYMP and POLG ); EDNRB, EDN3 , and SOX10 associated with Waardenburg syndrome with Hirschsprung disease; SGOL1 , RAD21 , FLNA , and L1CAM .…”
Section: Introductionmentioning
confidence: 99%
“…Lmods are expressed in different muscle tissues [3]. Lmod1 can be found in smooth muscle [4, 5] and was recently reported as a megacyst microcolon intestinal hypoperistaltis syndrome (MMIHS) disease gene in humans and mice [6]. Transcripts encoding the LMOD2 gene are present in fetal and adult heart and also in adult skeletal muscle [79].…”
Section: Introductionmentioning
confidence: 99%