Pseudo-obstruction–inducing ACTG2R257C alters actin organization and function

Hashmi, S.; Barka, Vasia; Yang, Chao; Schneider, Sabine; Svitkina, Tatyana; Heuckeroth, Robert O.

doi:10.1172/jci.insight.140604

Cited by 12 publications

(29 citation statements)

References 30 publications

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“…Small intestine idiopathic pseudo-obstruction is associated with a myriad of symptoms and motility abnormalities associated with diverse pathophysiology (207), dominated by actin filament deformation (208), but also loss of innervation and ICC to varying degrees. Small intestine pseudo-obstruction can be associated with nausea and vomiting, abdominal pain, distention, constipation, diarrhea, and urinary symptoms, associated with abnormal MMC propagation and persistent nonpropagating fasting activity (207).…”

Section: Chronic Idiopathic Pseudo-obstructionmentioning

confidence: 99%

Interstitial cells of Cajal and human colon motility in health and disease

Huizinga

Hussain

Chen

2021

American Journal of Physiology-Gastrointestinal and Liver Physi

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Our understanding of human colonic motility, and autonomic reflexes that generate motor patterns, has increased markedly through high-resolution manometry. Details of the motor patterns are emerging related to frequency and propagation characteristics that allow linkage to interstitial cells of Cajal (ICC) networks. In studies on colonic motor dysfunction requiring surgery, ICC are almost always abnormal or significantly reduced. However, there are still gaps in our knowledge about the role of ICC in the control of colonic motility and there is little understanding of a mechanistic link between ICC abnormalities and colonic motor dysfunction. This review will outline the various ICC networks in the human colon and their proven and likely associations with the enteric and extrinsic autonomic nervous systems. Based on our extensive knowledge of the role of ICC in the control of gastrointestinal motility of animal models and the human stomach and small intestine, we propose how ICC networks are underlying the motor patterns of the human colon. The role of ICC will be reviewed in the autonomic neural reflexes that evoke essential motor patterns for transit and defecation. Mechanisms underlying ICC injury, maintenance, and repair will be discussed. Hypotheses are formulated as to how ICC dysfunction can lead to motor abnormalities in slow transit constipation, chronic idiopathic pseudo-obstruction, Hirschsprung's disease, fecal incontinence, diverticular disease, and inflammatory conditions. Recent studies on ICC repair after injury hold promise for future therapies.

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Section: Chronic Idiopathic Pseudo-obstructionmentioning

confidence: 99%

Interstitial cells of Cajal and human colon motility in health and disease

Huizinga

Hussain

Chen

2021

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Our patient only displayed symptoms of intestinal pseudo‐obstruction (Figure 1A) and mild left hydronephrosis (Figure 1B, pelvic‐calyceal separation of 5 mm), without the other two typical symptoms of MMIHS. However, MMIHS and PIPO both belong to the hereditary visceral myopathies with a common pathological basis of impaired contraction capacity of visceral smooth muscle 20 1C,D) in the proband.…”

Section: Resultsmentioning

confidence: 99%

“…However, MMIHS and PIPO both belong to the hereditary visceral myopathies with a common pathological basis of impaired contraction capacity of visceral smooth muscle. 20 Thus, we revisited the WES data to search for potential mutations in LMOD1 and successfully revealed two heterozygous missense variants, c.1106C>T (p.T369M) and c.1262G>A (p.R421H) (Figure 1C,D) in the proband. Sanger sequencing results confirmed the cosegregation of the variants with the PIPO phenotype in this family.…”

Section: Lmod1 Variants Segregate With the Disease Phenotypementioning

confidence: 99%

Loss‐of‐function variants within LMOD1 actin‐binding site 2 cause pediatric intestinal pseudo‐obstruction by impairing protein stability and actin nucleation

Liu

Chen

et al. 2022

The FASEB Journal

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The leiomodin1 (LMOD1) gene, encoding a potent actin nucleator, was recently reported as a potential pathogenic gene of megacystis‐microcolon‐intestinal hypoperistalsis syndrome (MMIHS, OMIM 619362). However, only a single patient has been reported to have LMOD1 mutations, and the underlying pathogenic mechanism remains unknown. Here, we described a male infant with LMOD1 mutations presenting typical symptoms of pediatric intestinal pseudo‐obstruction (PIPO) but without megacystis and microcolon. Two compound heterozygous missense variants (c.1106C>T, p.T369M; c.1262G>A, p.R421H) were identified, both affecting highly conserved amino acid residues within the second actin‐binding site (ABS2) domain of LMOD1. Expression analysis showed that both variants resulted in significantly reduced protein amounts, especially for p.T369M, which was almost undetectable. The reduction was only partially rescued by the proteasome inhibitor MG‐132, indicating that there might be proteasome‐independent pathways involved in the degradation of the mutant proteins. Molecular modeling showed that variant p.T369M impaired the local protein conformation of the ABS2 domain, while variant p.R421H directly impaired the intermolecular interaction between ABS2 and actin. Accordingly, both variants significantly damaged LMOD1‐mediated actin nucleation. These findings provide further human genetic evidence supporting LMOD1 as a pathogenic gene underlying visceral myopathy including PIPO and MMIHS, strengthen the critical role of ABS2 domain in LMOD1‐mediated actin nucleation, and moreover, reveal an unrecognized role of ABS2 in protein stability.

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“…To date, only four studies (15,24,44,64) examined the phenotype of disease-causing ACTG2 variants using immortalized cancer cell lines. There are no published animal models.…”

Section: Gamma Smooth Muscle Actinmentioning

confidence: 99%

“…To increase biological relevance, our recent study of the ACTG2 R257C mutation employed human intestinal smooth muscle cells (HISMCs) and included extensive quantitative analysis (64). We demonstrated that ACTG2 R257C formed fewer, shorter, thinner, and less branched ACTG2-containing filament bundles compared with WT ACTG2.…”

Section: Gamma Smooth Muscle Actinmentioning

confidence: 99%

Visceral myopathy: clinical syndromes, genetics, pathophysiology, and fall of the cytoskeleton

Hashmi

Ceron

Heuckeroth

2021

American Journal of Physiology-Gastrointestinal and Liver Physi

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Visceral smooth muscle is a crucial component of the walls of hollow organs like the gut, bladder, and uterus. This specialized smooth muscle has unique properties that distinguish it from other muscle types and that facilitate robust dilation and contraction. Visceral myopathies are diseases where severe visceral smooth muscle dysfunction prevents efficient movement of air and nutrients though the bowel, impairs bladder emptying, and affects normal uterine contraction and relaxation, particularly during pregnancy. Disease severity exists along a spectrum. The most debilitating defects cause highly dysfunctional bowel, reduced intrauterine colon growth (microcolon), and bladder emptying defects requiring catheterization, a condition called Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIHS). People with MMIHS often die early in childhood. When the bowel is the main organ affected and microcolon is absent, the condition is known as myopathic chronic intestinal pseudo-obstruction (CIPO). Visceral myopathies like MMIHS and myopathic CIPO are most commonly caused by mutations in contractile apparatus cytoskeletal proteins. Here, we review visceral myopathy-causing mutations and normal functions of these disease-associated proteins. We propose molecular, cellular, and tissue-level models that may explain clinical and histopathological features of visceral myopathy and hope these observations prompt new mechanistic studies.

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Pseudo-obstruction–inducing ACTG2R257C alters actin organization and function

Cited by 12 publications

References 30 publications

Interstitial cells of Cajal and human colon motility in health and disease

Interstitial cells of Cajal and human colon motility in health and disease

Loss‐of‐function variants within LMOD1 actin‐binding site 2 cause pediatric intestinal pseudo‐obstruction by impairing protein stability and actin nucleation

Visceral myopathy: clinical syndromes, genetics, pathophysiology, and fall of the cytoskeleton

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