Compound heterozygous loss of function variants in <i>MYL9</i> in a child with megacystis–microcolon–intestinal hypoperistalsis syndrome

Kandler, Justin L; Sklirou, Evgenia; Woerner, Audrey C.; Walsh, Leslie; Cox, Eleina; Xue, Yuan

doi:10.1002/mgg3.1516

Cited by 14 publications

(10 citation statements)

References 22 publications

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“…compound heterozygous loss of function mutations [25]. Bronchopulmonary dysplasia was also observed in one of these patients [25]. These phenotypes in the intestine, bladder and lung are consistent with those seen in Myl9 -/mice.…”

Section: Plos Onesupporting

confidence: 72%

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MYL9 deficiency is neonatal lethal in mice due to abnormalities in the lung and the muscularis propria of the bladder and intestine

et al. 2022

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Class II myosin complexes are responsible for muscle contraction as well as other non-sarcomeric contractile functions in cells. Myosin heavy chain molecules form the core of these structures, while light chain molecules regulate their stability and function. MYL9 is a light chain isoform that is thought to regulate non-sarcomeric myosin. However, whether this in only in specific cell types or in all cells remains unclear. To address this, we generated MYL9 deficient mice. These mice die soon after birth with abnormalities in multiple organs. All mice exhibited a distended bladder, shortening of the small intestine and alveolar overdistension in the lung. The Myl9 allele in these mice included a LacZ reporter knockin that allowed for mapping of Myl9 gene expression. Using this reporter, we show that MYL9 expression is restricted to the muscularis propria of the small intestine and bladder, as well as in the smooth muscle layer of the bronchi in the lung and major bladder vessels in all organs. This suggests that MYL9 is important for the function of smooth muscle cells in these organs. Smooth muscle dysfunction is therefore likely to be the cause of the abnormalities observed in the intestine, bladder and lung of MYL9 deficient mice and the resulting neonatal lethality.

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Section: Plos Onesupporting

confidence: 72%

“…compound heterozygous loss of function mutations [25]. Bronchopulmonary dysplasia was also observed in one of these patients [25].…”

Section: Plos Onementioning

confidence: 92%

MYL9 deficiency is neonatal lethal in mice due to abnormalities in the lung and the muscularis propria of the bladder and intestine

et al. 2022

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“…Therefore, a mutation that eliminates or disrupts MYL9 would likely reduce SMC contractility. There are two reported MYL9 mutations associated with MMIHS (12,36,57). One mutation is a large homozygous deletion that removes the last exon (exon 4) from the two MYL9 transcripts (36).…”

Section: Myosin Light Chainmentioning

confidence: 99%

“…One mutation is a large homozygous deletion that removes the last exon (exon 4) from the two MYL9 transcripts (36). The second is a biallelic compound heterozygous mutation that removes exon 4 on one allele and causes a 9 bp deletion that removes canonical splice donor site at exon 2 from the second allele (57). It is not yet known if these MYL9 mutations lead to loss of rMLC function or reduced rMLC abundance.…”

Section: Myosin Light Chainmentioning

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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“…Pathogenic variation in ACTG2 disrupts this crucial function and has been estimated to account for ∼60% of VM cases ( Assia Batzir et al 2019 ). Several other genes have been implicated in VM, including myosin subunits MYH11 and MYL9 , and proteins involved in the actin–myosin interaction such as LMOD1 and MYLK ( Ambartsumyan 1993 ; Ravenscroft et al 2018 ; Kandler et al 2020 ). Enteric neuropathies such as Hirschsprung disease can also lead to CIPO ( Ambartsumyan 1993 ).…”

Section: Introductionmentioning

confidence: 99%

Expanding the genotypic spectrum of ACTG2-related visceral myopathy

James

Lau

Shayan

et al. 2021

Cold Spring Harb Mol Case Stud

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Visceral myopathies (VMs) encompass a spectrum of disorders characterized by chronic disruption of gastrointestinal function, with or without urinary system involvement. Pathogenic missense variation in smooth muscle γ-actin gene ( ACTG2 ) is associated with autosomal dominant VM. Whole-genome sequencing of an infant presenting with chronic intestinal pseudo-obstruction revealed a homozygous 187 bp (c.589_613 + 163del188) deletion spanning the exon 6–intron 6 boundary within ACTG2 . The patient's clinical course was marked by prolonged hospitalizations, multiple surgeries, and intermittent total parenteral nutrition dependence. This case supports the emerging understanding of allelic heterogeneity in ACTG2 -related VM, in which both biallelic and monoallelic variants in ACTG2 are associated with gastrointestinal dysfunction of similar severity and overlapped clinical presentation. Moreover, it illustrates the clinical utility of rapid whole-genome sequencing, which can comprehensively and precisely detect different types of genomic variants including small deletions, leading to guidance of clinical care decisions.

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Compound heterozygous loss of function variants in MYL9 in a child with megacystis–microcolon–intestinal hypoperistalsis syndrome

Cited by 14 publications

References 22 publications

MYL9 deficiency is neonatal lethal in mice due to abnormalities in the lung and the muscularis propria of the bladder and intestine

MYL9 deficiency is neonatal lethal in mice due to abnormalities in the lung and the muscularis propria of the bladder and intestine

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

Expanding the genotypic spectrum of ACTG2-related visceral myopathy

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