Mutation in Actin γ‐2 Responsible for Megacystis Microcolon Intestinal Hypoperistalsis Syndrome in 4 Chinese Patients

Lü, Wei; Xiao, Yongtao; Huang, Jiejie; Tao, Yijing; Yan, Wei; Lu, Lina; Yi, Cao; Cai, Wei

doi:10.1097/mpg.0000000000001204

Cited by 27 publications

(20 citation statements)

References 14 publications

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“…We and others identified ACTG2 as the first single gene for the disease traits of visceral myopathy (Lehtonen et al, ), and MMIHS/CIPO (Thorson et al, ; Wangler et al, ). Subsequent reports, supported by functional data from mouse models, established the important role of ACTG2 in these disorders (Halim et al, ; Holla, Bock, Busk, & Isfoss, ; Klar et al, ; Lu et al, ; Matera et al, ; Milunsky, Baldwin, et al, ; Milunsky, Lazier, et al, ; Moreno et al, ; Tuzovic et al, ; Whittington, Poole, Dutta, & Munn, ). ACTG2 encodes a muscle actin isoform predominantly expressed in the intestinal smooth muscle (Miwa et al, ; Szucsik & Lessard, ) which, together with myosin, comprises the apparatus responsible for muscle contraction and relaxation.…”

Section: Introductionmentioning

confidence: 89%

Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy

et al. 2019

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Visceral myopathy with abnormal intestinal and bladder peristalsis includes a clinical spectrum with megacystis-microcolon intestinal hypoperistalsis syndrome and chronic intestinal pseudo-obstruction. The vast majority of cases are caused by dominant variants in ACTG2; however, the overall genetic architecture of visceral myopathy has not been well-characterized. We ascertained 53 families, with visceral myopathy based on megacystis, functional bladder/gastrointestinal obstruction, or microcolon. A combination of targeted ACTG2 sequencing and exome sequencing was used. We report a molecular diagnostic rate of 64% (34/53), of which 97% (33/34) is attributed to ACTG2. Strikingly, missense mutations in five conserved arginine residues involving CpG dinucleotides accounted for 49% (26/53) of disease in the cohort. As a group, the ACTG2-negative cases had a more favorable clinical outcome and more restricted disease. Within the ACTG2-positive group, poor outcomes (characterized by total parenteral nutrition dependence, death, or transplantation) were invariably due to one of the arginine missense alleles. Analysis of specific residues suggests a severity spectrum of p.Arg178>p.Arg257>p.Arg40 along with other less-frequently reported sites p.Arg63 and p.Arg211. These results provide genotype-phenotype correlation for ACTG2-related disease and demonstrate the importance of arginine missense changes in visceral myopathy. K E Y W O R D SACTG2, dysmotility, megacystis-microcolon intestinal hypoperistalsis, smooth muscle, visceral myopathy

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Section: Introductionmentioning

confidence: 89%

Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy

et al. 2019

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“…After the submission of this manuscript, two articles were published in on line version describing patients with ACTG2‐related disorder: MMIHS [Lu et al, ] and MMIHS, and CIPO [Matera et al, ].…”

Section: Addendum Added During Revision Of the Manuscriptmentioning

confidence: 99%

Visceral myopathy: Clinical and molecular survey of a cohort of seven new patients and state of the art of overlapping phenotypes

Moreno

Metze

Lomazi

et al. 2016

American J of Med Genetics Pt A

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Visceral motility dysfunction is a key feature of genetic disorders such as megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS, MIM moved from 249210 to 155310), chronic intestinal pseudo-obstruction (CIPO, MIM609629), and multisystemic smooth muscle dysfunction syndrome (MSMDS, MIM613834). The genetic bases of these conditions recently begun to be clarified with the identification of pathogenic variants in ACTG2, ACTA2, and MYH11 in individuals with visceral motility dysfunction. The MMIHS was associated with the heterozygous variant in ACTG2 and homozygous variant in MYH11, while the heterozygous variant in ACTA2 was observed in patients with MSMDS. In this study, we describe the clinical data as well as the molecular investigation of seven individuals with visceral myopathy phenotypes. Five patients presented with MMIHS, including two siblings from consanguineous parents, one had CIPO, and the other had MSMDS. In three individuals with MMIHS and in one with CIPO we identified heterozygous variant in ACTG2, one being a novel variant (c.584C>T—p.Thr195Ile). In the individual with MSMDS we identified a heterozygous variant in ACTA2. We performed the whole-exome sequencing in one sibling with MMIHS and her parents; however, the pathogenic variant responsible for her phenotype could not be identified. These results reinforce the clinical and genetic heterogeneity of the visceral myopathies. Although many cases of MMIHS are associated with ACTG2 variants, we suggest that other genes, besides MYH11, could cause the MMIHS with autosomal recessive pattern.

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“…Autosomal recessive inheritance of CIPO is highly likely in children of consanguineous unions 17,18 or in affected siblings with healthy parents (bearing in mind gonadal mosaicism). A homozygous pathogenic variant in the RAD21 gene was reported in one consanguineous family.…”

Section: Discussionmentioning

confidence: 99%

Diagnosis of Chronic Intestinal Pseudo‐obstruction and Megacystis by Sequencing the ACTG2 Gene

Milunsky

Baldwin

Zhang

et al. 2017

J. pediatr. gastroenterol. nutr.

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Objectives The diagnosis of chronic intestinal pseudo-obstruction (CIPO) has depended on clinical features, manometry, and imaging. This report aimed to determine the efficacy of sequencing the ACTG2 gene for diagnosis. In addition, the goal was to determine how often a mutation would be found in our randomly collected cohort of probands and those probands published previously. Methods Whole exome sequencing was performed in 4 probands with CIPO. Subsequently, only the ACTG2 gene was sequenced in another 24 probands (total 28). We analyzed published data of 83 probands plus our 28 [total 111] and determined how many had pathogenic variants and the precise genotype. Results Whole exome and Sanger sequencing revealed a pathogenic variant in the ACTG2 gene in 4/28 of our probands and in 45 out of 83 published probands [49/111(44.1%)]. Moreover, a mutational hotspot in the ACTG2 gene was recognized. Genetic heterogeneity is evident. Conclusion Pooled gene sequencing results from one individual in each of 111 families enabled a precise diagnosis of an ACTG2 mutation in 49 (44%). The benefit to patients and families of early confirmation of a motility disorder not only helps avoid unnecessary intervention, but also enables institution of appropriate treatments and avoidance of secondary disorders such as malnutrition and poor growth. Knowledge of a pathogenic variant in a parent, with a 50% risk of recurrence, provides an opportunity for genetic counseling.

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Mutation in Actin γ‐2 Responsible for Megacystis Microcolon Intestinal Hypoperistalsis Syndrome in 4 Chinese Patients

Cited by 27 publications

References 14 publications

Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy

Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy

Visceral myopathy: Clinical and molecular survey of a cohort of seven new patients and state of the art of overlapping phenotypes

Diagnosis of Chronic Intestinal Pseudo‐obstruction and Megacystis by Sequencing the ACTG2 Gene

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