Alternative titles; symbols
HGNC Approved Gene Symbol: ACTG2
Cytogenetic location: 2p13.1 Genomic coordinates (GRCh38): 2:73,893,008-73,919,865 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p13.1 | Megacystis-microcolon-intestinal hypoperistalsis syndrome 5 | 619431 | Autosomal dominant | 3 |
| Visceral myopathy 1 | 155310 | Autosomal dominant | 3 |
Miwa et al. (1991) isolated recombinant phages that carried the human smooth muscle (enteric) gamma-actin gene (which they symbolized ACTSG) from human genomic DNA libraries.
Ueyama et al. (1995) isolated genomic clones containing the ACTG2 gene, which has also been symbolized ACTA3.
Szucsik and Lessard (1995) characterized the mouse smooth muscle (enteric) gamma-actin gene. It represented the largest isoactin gene characterized to that time, measuring over 23,000 bp from the transcription start site to the polyadenylation signal. The gene encodes a mature actin protein of 374 amino acids.
Thorson et al. (2014) performed RT-PCR in various mouse tissues and observed higher transcription levels of Actg2 in tissues containing smooth muscle, particularly the intestines and bladder.
Halim et al. (2016) assessed expression of ACTG2 in human jejunum and ileum at weeks 9, 11 and 22 of embryonic development and at the neonatal stage. At all developmental stages, ACTG2 was abundantly expressed in the cytoplasm of smooth muscle cells, including smooth muscle cells of the muscularis mucosa, the inner circular and outer longitudinal layers of the muscularis propria, and in vascular smooth muscle cells of the intestine. ACTG2 was also detected in myofibroblast cells of the mucosal layer, which had previously been reported to express only ACTA2 (102620); the authors stated that it was possible that their antibody might recognize both the alpha and gamma smooth muscle actin isoforms.
Miwa et al. (1991) determined that the human ACTG2 gene contains one 5-prime untranslated exon and 8 coding exons extending for 27 kb.
Szucsik and Lessard (1995) determined that the mouse Actg2 gene contains 9 exons.
From the characterized molecular structures of the 6 human actin isoform genes, Miwa et al. (1991) proposed a hypothesis of the evolutionary pathway of the actin gene family. Each of the 5 other actin genes maps to a separate chromosome.
Miwa et al. (1991) mapped the human ACTG2 gene to chromosome 2 by study of rodent-human somatic cell hybrids. Ueyama et al. (1995) mapped the ACTG2 gene to 2p13.1 by fluorescence in situ hybridization.
Ueyama et al. (1995) demonstrated that the HindIII RFLP in the first intron of the ACTG2 gene is due to the presence/absence of a 24-bp sequence harboring a HindIII restriction site. A biallelic system was found to have allelic frequencies of 45 (HindIII-minus):55 (HindIII-Plus).
By studying lymphoblastoid cells, Cheung et al. (2003) studied natural variation in human gene expression. The variance ratio of 813 genes ranged from 0.4 to 64 with a median value of 2.5. In an examination of the actual variances of expression levels of ACTG2 and 4 other highly variable genes, ACTG2 showed the highest variance ratio; in 35 persons studied, its expression level varied by a factor of 17. In an examination of the gene transcript levels of ACTG2 and 4 other highly variable genes among 3 groups of people (49 unrelated individuals, offspring from 5 CEPH families, and 10 pairs of monozygotic twins), the variance among unrelated individuals was 3 to 11 times greater than that between monozygotic twins, and the variance among sibs was 2 to 5 times greater than that between twins.
In a 3-generation Finnish family with visceral myopathy-1 (VSCM1; 155310), Lehtonen et al. (2012) identified a missense mutation in the ACTG2 gene (R148S; 102545.0001). The mutation, which segregated with disease, was not found in 280 Finnish controls.
In a 55-year-old Norwegian woman with chronic intestinal pseudoobstruction due to biopsy-proven visceral myopathy, Holla et al. (2014) performed next-generation sequencing and identified heterozygosity for the ACTG2 R148S mutation, which was not found in her unaffected mother.
In a 12-year-old girl and an unrelated male infant with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS5; 619431), Thorson et al. (2014) identified heterozygosity for de novo missense mutations in the ACTG2 gene, R178L (102545.0002) and R178C (102545.0003), respectively.
In a cohort of 27 probands with MMIHS and intestinal pseudoobstruction, Wangler et al. (2014) identified 15 who had heterozygous missense variants in the ACTG2 gene (see, e.g., 102545.0003-102545.0009), including 10 apparent de novo mutations. The authors suggested that ACTG2 is responsible for a spectrum of smooth muscle disease.
Halim et al. (2016) screened a cohort of 11 patients with typical features of MMIHS for mutations in the ACTG2 gene and identified heterozygous mutations in 8 patients with sporadic disease (102545.0002-102545.0004, 102545.0006, and 102545.0010). The mutations were shown to have arisen de novo in the 3 probands for whom familial DNA was available. Halim et al. (2016) stated that visceral myopathy (VSCM) and MMIHS are clinically separate disorders with overlapping features, in which the 2 main differences are age of onset, with MMIHS being diagnosed prenatally due to recognizable bladder distention and VSCM occurring during adolescence, and disease severity, with most MMIHS patients surviving only a few days or months after birth. However, they noted that their results showed no indication that MMIHS and VSCM are pathophysiologically different disorders.
From a cohort of 7 Brazilian children with 'visceral myopathy phenotypes,' Moreno et al. (2016) identified 3 unrelated patients with MMIHS who were heterozygous for missense mutations in ACTG2 (102545.0002, 102545.0003, and 102545.0013). Two of the patients had died despite supportive therapy, and the third was alive on total parenteral nutrition at age 5 months. The mutations were de novo in each proband, as they were not found in the respective parents. The authors also identified heterozygosity for a missense mutation in ACTG2 (T195I; 102545.0011) in a 5-year-old girl with a 3-year history of chronic intestinal pseudoobstruction.
From a cohort of 28 probands who had CIPO with or without megacystis, Milunsky et al. (2017) identified 4 probands with heterozygous mutations in the ACTG2 gene: 3 probands, including 1 with an affected family member (family A), had the R257C mutation (102545.0007), and 1 proband and 2 affected family members (family B) carried the R40H mutation (102545.0005). The authors noted that of 49 reported probands with CIPO, 33 (73.3%) had a pathogenic variant at either R178 or R257, and they suggested that those amino acids likely represent mutational hotspots in ACTG2.
In a cohort of 21 patients with primary CIPO associated with visceral myopathy from 17 Australasian families, Ravenscroft et al. (2018) sequenced the ACTG2 gene and identified heterozygosity for a missense mutation (R148L; 102545.0012) in affected members of a 3-generation family. Four unrelated patients were heterozygous for the previously reported R257C mutation (102545.0007), including 1 who was diagnosed within the first 2 months of life with 'congenital megacolon and megacystis syndrome (CMM).' Two unrelated patients had mutations at codon R40: 1 who was diagnosed in utero with CMM was heterozygous for R40H (102545.0005), and 1 who was diagnosed in utero with MMIHS was heterozygous for R40C (102545.0006).
Matera et al. (2021) reported 11 patients from 9 families with neonatal/infantile gastrointestinal motility disorder and heterozygous mutations in the ACTG2 gene (see, e.g., 102545.0005 and 102545.0007).
Associations Pending Confirmation
Monies et al. (2017) reported a 16-year-old girl (15DG1406) with 'severe visceral myopathy' who was homozygous for a nonsense mutation in ACTG2 (R168X). An unaffected sister was also homozygous for the variant; she experienced chronic constipation, which was also present in the mother and another sister, who were both heterozygous for R168X. An older sister had died at age 24 years due to intestinal obstruction and perforation, but her mutation status was unknown.
In 2 sisters (FP8.A1 and FP8.A2) with severe neonatal/infantile gastrointestinal motility disorder, including CIPO and megacystis, Matera et al. (2021) identified homozygosity for an R366W variant in the ACTG2 gene. The authors noted that R366W was not present in the gnomAD database. No segregation studies were done.
Assia Batzir et al. (2020) studied a cohort of 53 families with MMIHS, including the 15 ACTG2 mutation-positive families previously reported by Wangler et al. (2014). Mutations in the ACTG2 gene were present in 33 (62%) of the families (see, e.g., 102545.0002, 102545.0003, 102545.0005-102545.0008, and 102545.0010). The majority of individuals who tested positive for ACTG2 exhibited the classic MMIHS phenotype, including a combination of symptoms suggesting bladder and intestinal dysmotility. The authors noted that ACTG2-positive patients were more likely to have severe disease than ACTG2-negative patients. Within the ACTG2-positive group, poor outcomes including total parenteral nutrition dependence, multiorgan transplantation, or death were invariably associated with arginine missense alleles. Analysis of specific residues suggested a spectrum of severity, in which R178 involvement causes the most severe disease, with R257 next in severity, followed by R40.
In 7 affected individuals from over 3 generations of a Finnish family with visceral myopathy (VSCM1; 155310), Lehtonen et al. (2012) identified heterozygosity for a c.442C-A transversion in exon 5 of the ACTG2 gene, resulting in an arg148-to-ser (R148S) substitution at a highly conserved residue. A 19-year-old member of the family who had only mild abdominal pain and distention and had not yet been diagnosed with visceral myopathy also carried the mutation, but it was not found in 280 Finnish controls. Intestinal smooth muscle from patients showed reduced levels of cytoplasmic ACTG2 compared to controls, as well as abnormal accumulation of the protein in intracellular inclusion bodies. Functional analysis in sarcoma cells showed that the R148S mutant inhibits incorporation of actin monomers into filamentous structures, and gel contraction assay showed substantially decreased contractility with the mutant compared to wildtype.
In a 55-year-old Norwegian woman with chronic intestinal pseudoobstruction due to biopsy-proven visceral myopathy, Holla et al. (2014) performed next-generation sequencing and identified heterozygosity for the ACTG2 R148S mutation, which was not found in her unaffected mother.
Variant Function
In studies in transfected U2OS cells, Halim et al. (2016) showed that whereas wildtype ACTG2 could incorporate into actin filaments, the R148S mutant did not. In addition, the mutant showed a reduction in contractility compared to wildtype ACTG2, but the difference was not statistically significant.
In a 12-year-old girl who had neonatal megacystis, hydronephrosis, and malrotation and pseudoobstruction of the intestine (MMIHS5; 619431), Thorson et al. (2014) identified heterozygosity for a de novo c.533G-T transversion in the ACTG2 gene, resulting in an arg178-to-leu (R178L) substitution at a highly conserved residue within the hinge separating domains III and IV. The mutation was not present in her unaffected parents or in the Exome Variant Server database. Confocal scans of COS-7 cells showed colocalization of wildtype ACTG2 with actin filaments, whereas the R178L mutant showed diffuse localization and poor association with actin filaments. Cell contractility assessment with the mutant showed decreased collagen contraction capacity.
In a female infant (S5) with megacystis and polyhydramnios detected prenatally, who also had microcolon, hypoperistalsis, and malrotation and died at age 8 months of multiple organ failure, Halim et al. (2016) identified heterozygosity for the R178L mutation in the ACTG2 gene. The mutation was shown to have arisen de novo, as it was not found in either of her unaffected parents. The variant was not present in the 1000 Genomes Project or ExAC databases. Studies in transfected U2OS cells showed that whereas wildtype ACTG2 could incorporate into actin filaments, the R178L mutant did not. In addition, there was a significant reduction in contractility with the R178L mutant compared to wildtype.
In a Brazilian male infant (patient 5) with MMIHS, who was alive at age 5 months on total parenteral nutrition, Moreno et al. (2016) identified heterozygosity for the R178L mutation in ACTG2. The mutation was shown to have arisen de novo, as it was not present in the proband's unaffected parents.
From a cohort of 53 families with MMIHS, Assia Batzir et al. (2020) identified 1 (Fam39) in which the proband was heterozygous for the R178L mutation in the ACTG2 gene. The mutation arose de novo.
In a male infant with megacystis and intestinal pseudoobstruction (MMIHS5; 619431), Thorson et al. (2014) identified heterozygosity for a de novo c.532C-T transition in the ACTG2 gene, resulting in an arg178-to-cys (R178C) substitution at a highly conserved residue within the hinge separating domains III and IV. Confocal scans of COS-7 cells showed colocalization of wildtype ACTG2 with actin filaments, whereas the R178C mutant showed diffuse localization and poor association with actin filaments. Cell contractility assessment with the mutant showed decreased collagen contraction capacity.
In a 3-year-old boy (family 29) prenatally diagnosed with fetal megacystis, Wangler et al. (2014) identified heterozygosity for a de novo R178C mutation in exon 6 of the ACTG2 gene. The patient had surgery for malrotation shortly after birth and required 18 hours of total parenteral nutrition per day and bladder catheterization every 4 to 6 hours. He also had an undescended testicle.
In a male infant (S3) and 2 female infants (S7 and S8) with MMIHS, Halim et al. (2016) identified heterozygosity for the R178C mutation in the ACTG2 gene. The mutation was shown to have arisen de novo in the male proband, as it was not found in either of his unaffected parents; DNA was unavailable from the parents of the female probands. The R178C variant was not found in the 1000 Genomes Project or ExAC databases. The male proband was diagnosed prenatally with bilateral megaureter and hydronephrosis, and abdominal wall dehiscence. In addition to megacystis and microcolon, he had documented hypoperistalsis, malrotation, and an undescended testis. All 3 infants were deceased; little information was available for S7 and S8, but S3 died at 5 days of life when treatment was discontinued. Studies in transfected U2OS cells showed that whereas wildtype ACTG2 could incorporate into actin filaments, the R178C mutant did not. In addition, there was a significant reduction in contractility with the R178C mutant compared to wildtype.
In a Brazilian male infant (patient 3) with MMIHS, who died at age 7 months, Moreno et al. (2016) identified heterozygosity for the R178C mutation in ACTG2. The mutation arose de novo, as it was not present in the proband's unaffected parents.
In a 6-year-old girl (family 35) prenatally diagnosed with fetal megacystis (MMIHS5; 619431), Wangler et al. (2014) identified heterozygosity for a de novo c.533G-A transition in exon 6 of the ACTG2 gene, resulting in an arg178-to-his (R178H) substitution. At birth, the patient had bilious vomiting and was found to have malrotation and microcolon; she required TPN and bladder catheterization throughout her life. Wangler et al. (2014) also detected heterozygosity for the R178H mutation in the patient's mother and in another patient; no clinical information was provided for the latter 2 patients.
In 2 female infants (S2 and S4) with MMIHS5, Halim et al. (2016) identified heterozygosity for the R178H mutation in the ACTG2 gene. The mutation was shown to have arisen de novo in proband S2; DNA was not available from the parents of S4. Both patients had megacystis and microcolon with documented hypoperistalsis; S4 also had malrotation. Both patients were deceased. Studies in transfected U2OS cells showed that whereas wildtype ACTG2 could incorporate into actin filaments, the R178H mutant did not. In addition, there was a significant reduction in contractility with the R178H mutant compared to wildtype.
Visceral Myopathy 1
In 5 affected individuals from over 4 generations of a family (Fam34) with constipation, intestinal dysmotility, megacystis, and megacolon (VSCM1; 155310), Wangler et al. (2014) identified heterozygosity for a c.119G-A transition in exon 2 of the ACTG2 gene, resulting in an arg40-to-his (R40H) substitution. The proband, a 1-year-old boy with fetal megacystis, underwent postnatal surgery for malrotation; although he could feed orally, he required bladder catheterization. His father and paternal grandmother, both of whom also carried the mutation, had lifelong constipation and dysmotility; the father underwent surgery for gastrointestinal obstruction and suspected superior mesenteric artery occlusion, whereas the paternal grandmother underwent removal of megacolon in adulthood. Wangler et al. (2014) also detected heterozygosity for a de novo R40H mutation in a 16-year-old boy (Fam12) who had fetal megacystis and was treated by prenatal bladder diversion; after birth, he was fed by mouth but had frequent constipation and underwent colostomy at age 2 years. He was diagnosed with hollow visceral myopathy. Manometric studies at 2 and 4 years of age showed no peristaltic activity. At age 16 years, he had lifetime dependence on bladder catheterization but was able to tolerate meals.
Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome 5
In 3 affected individuals from a family (family B) with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS5; 619431), Milunsky et al. (2017) identified heterozygosity for the R40H mutation in the ACTG2 gene. Onset of disease was prenatal or at birth and all required long-term bladder catheterization for megacystis. One patient died at age 6 months; the other 2 were living at 3 years and 28 years of age. None of the 3 patients had microcolon.
In a boy (patient 2) who was diagnosed with congenital megacolon and megacystis and died at age 4 years, Ravenscroft et al. (2018) identified heterozygosity for the R40H mutation in the ACTG2 gene. Megacystis was diagnosed prenatally, and postnatal symptoms included abdominal pain and distension, nausea and vomiting, constipation, and malnutrition. He was on parenteral nutrition.
In a 10-year-old girl with prenatal onset of megacystis, who also had malrotation and gastrectasis and was dependent on parenteral nutrition, Matera et al. (2021) identified heterozygosity for the R40H mutation in ACTG2. Parental DNA was unavailable for analysis.
In a 16-year-old girl (family 26) with fetal megacystis who underwent vesicostomy at birth and who also had microcolon (MMIHS5; 610431) requiring total parenteral nutrition (TPN), Wangler et al. (2014) identified a de novo c.118C-T transition in exon 2 of the ACTG2 gene, resulting in an arg40-to-cys (R40C) substitution. Despite a period of relative improvement beginning at age 4 years during which she did not require TPN, after age 13, she developed complications, including bowel perforation and multiple infections. At 16 years of age, she was dependent on TPN for 12 hours a day, with additional feedings by gastrostomy, and required bladder catheterization.
In a 24-year-old woman (S6) who was diagnosed prenatally with megacystis and also had microcolon, documented hypoperistalsis, and malrotation, Halim et al. (2016) identified heterozygosity for the R40C mutation in the ACTG2 gene. The mutation was shown to have arisen de novo in the proband, as it was not found in either of her unaffected parents. The variant was not present in the 1000 Genomes Project or ExAC databases. The proband was maintained on parenteral and enteral nutrition. Studies in transfected U2OS cells showed that whereas wildtype ACTG2 could incorporate into actin filaments, the R40C mutant did not. In addition, the mutant showed a reduction in contractility compared to wildtype ACTG2, but the difference was not statistically significant.
In a female fetus (patient 19) that showed abdominal distention, microcolon, and megacystis prenatally and was diagnosed with MMIHS, Ravenscroft et al. (2018) identified heterozygosity for the R40C mutation in the ACTG2 gene.
Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome 5
In 3 unrelated children (families 4, 25, 30) diagnosed either prenatally or in infancy with megacystis (MMIHS5; 619431), 2 of whom also had microcolon and 1 of whom also had intestinal malrotation, Wangler et al. (2014) identified a de novo c.769C-T transition in exon 7 of the ACTG2 gene, resulting in an arg257-to-cys (R257C) substitution. All 3 patients required total parenteral nutrition (TPN) and 2 required bladder catheterization. One patient developed chronic pancreatitis and died at age 11 years due to infectious complications; another underwent transplantation of small bowel, stomach, pancreas, and colon at 7 years of age and was clinically well at age 13 years, with an ileostomy and a regimen of double-voiding twice a day. The third patient was TPN- and catheterization-dependent at 1 year of age. Wangler et al. (2014) also identified the R257C mutation in a girl with prenatal megacystis, who had a period of normal bowel and bladder function in the first years of life, followed by progressive pseudoobstruction, and who died at 13 years of age. The mutation was inherited from her mother, for whom medical records were not available, but who was reported to have had irritable bowel syndrome.
In 4 patients from 3 families with chronic intestinal pseudoobstruction and megacystis that was present prenatally or at birth, Milunsky et al. (2017) identified heterozygosity for the R257C mutation in the ACTG2 gene. All were on long-term total parenteral nutrition; 2 patients died, at ages 2 years and 11.5 years, whereas the other 2 patients (from family A) were alive at ages 39 years and 6 years. None of the patients had microcolon.
Visceral Myopathy 1
In 4 unrelated Australasian children with visceral myopathy (VSCM1; 155310), Ravenscroft et al. (2018) identified heterozygosity for the R257C mutation in the ACTG2 gene. All patients were symptomatic in the first year of life; 3 were diagnosed with chronic intestinal pseudoobstruction and 1 with congenital megacolon and megacystis. All were alive, at 3, 11, 15, and 15 years of age, and 2 required total parental nutrition. In the 3 patients for whom parental DNA was available, the mutation was shown to have arisen de novo.
Matera et al. (2021) reported 3 unrelated children (SP2, SP6, and SP9), aged 5, 3, and 3.3 years, with prenatal/infantile gastrointestinal motility disorder and heterozygosity for the R257C mutation in ACTG2. Two were dependent on parenteral nutrition, and 1 was sustained on nocturnal enteral nutrition and highly monitored oral feeding. All 3 had megacystis, and 1 had colonic dilation.
In 2 sisters (fam19) with intestinal hypomotility and functional gastrointestinal obstruction that developed after infancy (VSCM1; 155310), Wangler et al. (2014) identified heterozygosity for a c.330C-A transversion in alternative exon 4 of the ACTG2 gene, resulting in a phe110-to-leu (F110L) substitution. One of the sisters had multiple abdominal surgeries for obstruction and intermittently required TPN from 17 years of age, but did not require bladder catheterization; the other sister experienced years of intestinal symptoms and underwent endoscopy, the results of which suggested gastroparesis, but did not have any surgery. The mutation was not found in their unaffected mother; no information was available regarding their deceased father.
In a 25-year-old man (family 16) who had fetal megacystis with absent abdominal wall musculature noted at birth (MMIHS5; 619431), Wangler et al. (2014) identified a de novo c.412T-A transversion in exon 5 of the ACTG2 gene, resulting in a tyr134-to-asn (Y134N) substitution. The patient was placed on total parenteral nutrition (TPN) in infancy and underwent surgeries for intestinal pseudoobstruction at ages 6 months and 4 years. Additional health issues included ventricular dysfunction, asthma, pectus excavatum requiring surgery, osteoporosis, and endocrine abnormalities.
In a woman (S1) diagnosed prenatally with megacystis, hydroureter, and hydronephrosis who also had hypoperistalsis, microcolon, and malrotation of the intestines (MMIHS5; 619431), Halim et al. (2016) identified heterozygosity for an arg63-to-gln (R63Q) substitution in the ACTG2 gene. She underwent multiorgan transplantation, but died at age 23 years.
In 3 families (Fam9, Fam42, and Fam51) with MMIHS5, Assia Batzir et al. (2020) identified heterozygosity for a c.188G-A transition (c.188G-A, NM_001615.3) in the ACTG2 gene, resulting in the R63Q substitution. In Fam9, the mutation was shown to have arisen de novo in the proband, whereas in Fam51, it was inherited from the mother, who exhibited uterine atony. No information was available from the parents in Fam42. The Fam9 proband had prune belly.
In a 5-year-old Brazilian girl (patient 6) with chronic intestinal pseudoobstruction (VSCM1; 155310), Moreno et al. (2016) identified heterozygosity for a c.584C-T transition in the ACTG2 gene, resulting in a thr195-to-ile (T195I) substitution. The mutation was not found in her unaffected mother, 100 control alleles, or public variant databases; DNA was unavailable from the father.
In 2 brothers and their 2 affected sons from a 3-generation family (family 1) with chronic intestinal pseudoobstruction (VSCM1; 155310), Ravenscroft et al. (2018) identified heterozygosity for a c.443G-T transversion (c.443G-T, NM_001615.3) in the ACTG2 gene, resulting in an arg148-to-leu (R148L) substitution. Age at onset of symptoms ranged from 20 to 40 years. The brothers' mother had a long history of gastrointestinal dysmotility, including megacolon and atonic bowel requiring total parenteral nutrition, but her DNA was not available for analysis.
In a Brazilian female infant (patient 4) who died at age 11 months with megacystis-microcolon-intestinal hypoperistalsis syndrome-5 (MMIHS5; 619431), Moreno et al. (2016) identified heterozygosity for a c.770G-A transition (c.770G-A, NM_001615) in the ACTG2 gene, resulting in an arg257-to-his (R257H) substitution. The mutation arose de novo, as it was not present in the proband's unaffected parents.
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