Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: MYH11
Cytogenetic location: 16p13.11 Genomic coordinates (GRCh38): 16:15,703,135-15,857,028 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.11 | Aortic aneurysm, familial thoracic 4 | 132900 | Autosomal dominant | 3 |
| Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 | 619351 | Autosomal recessive | 3 | |
| Visceral myopathy 2 | 619350 | Autosomal dominant | 3 |
Matsuoka et al. (1991, 1993) isolated a smooth muscle myosin heavy-chain gene from a human cDNA library. They confirmed it as a smooth muscle MHC gene by Northern blot hybridization and a partial DNA sequence analysis.
Deng et al. (1993) mapped the MYH11 gene to the middle of the short arm of chromosome 16 by fluorescence in situ hybridization. Southern blots of a panel of hybrids containing different portions of human chromosome 16 localized the gene to 16p13.13-p13.12. Studies of DNA from a CHO/mouse hybrid clone mapping panel showed that the gene was located on mouse chromosome 16.
MYH11/CBFB FUSION GENE
The pericentric inversion inv(16)(p13q22) is a characteristic abnormality associated with acute myeloid leukemia, most commonly of the M4Eo subtype. Liu et al. (1993) pinpointed the 16p and 16q breakpoints by yeast artificial chromosome and cosmid cloning and identified the 2 genes involved in the inversion. On 16p, the MYH11 gene was interrupted; on 16q, the inversion occurred near the end of the coding region for CBF-beta (121360), also known as PEBP2-beta, a subunit of a heterodimeric transcription factor regulating genes expressed in T cells. In all of 6 inv(16) patients tested, an in-frame fusion messenger RNA was demonstrated that connected the first 165 amino acids of CBFB with the tail region of MYH11. The repeated coiled coil of MYH11 may result in dimerization of the CBFB fusion protein, which in turn would lead to alterations in transcriptional regulation and contribute to leukemic transformation.
Castilla et al. (1999) showed that the fusion Cbfb-MYH11 blocks myeloid differentiation in mice and predisposes the mice to acute myelomonocytic leukemia when exposed to N-ethyl-N-nitrosourea (ENU), a potent DNA alkylating mutagen.
Huang et al. (2004), who referred to MYH11 as smooth muscle myosin heavy chain (SMMHC), investigated the molecular basis for the dominant inactivation of RUNX1 (151385) by the leukemogenic inversion of chromosome 16. They showed that, in the PEBP2-beta-SMMHC chimeric protein, the second heterodimerization domain is created by the fusion junction, enabling the chimeric protein to interact with RUNX1 at far greater affinity than PEBP2-beta and inactivate the RUNX1 function. To explain how heterozygous chimeric protein can inactivate homozygous RUNX1 near to completion, Huang et al. (2004) proposed a model for the chimeric protein that consists of a Y-shaped dimer with unpaired N-terminal halves followed by a coiled-coil for the C-terminal region.
In a 7-year-old girl with megacystis-microcolon-intestinal hypoperistalsis syndrome with impaired tonic pupil reaction (MMIHS2; 619351), who also had growth hormone deficiency and central hypothyroidism, Kloth et al. (2019) identified heterozygosity for a paternally inherited P127S mutation in the MYH11 gene, and a maternally inherited heterozygous 1.3-Mb deletion at chromosome 16p13.11, involving MHY11 and 14 other genes. The authors suggested that the father might be at increased risk for thoracic aortic aneurysm (see 132900) as a heterozygous carrier of the P127S missense variant, warranting regular cardiovascular follow-up.
Familial Thoracic Aortic Aneurysm 4
Familial clustering of common (isolated) thoracic aortic aneurysm/aortic dissection (TAAD), one of the most severe cardiovascular conditions in adults, is heterogeneous, with 1 locus having been mapped to chromosome 16p13.1-p12.2 (AAT4; 132900). The MYH11 gene is located in the critical linkage region for AAT4. Zhu et al. (2006) performed systematic mutation screening, which showed 2 heterozygous mutations affecting the same allele of MYH11 in the French kindred reported by Khau Van Kien et al. (2004, 2005). The first was a substitution at the splice donor site of intron 32 and the second was a missense mutation in exon 37, R1758Q (160745.0001). Both mutations were identified in all subjects carrying the disease haplotype, but neither was found in 340 normal chromosomes. A similar mutation analysis in an American family with a combination of thoracic aortic aneurysm and patent ductus arteriosus (Glancy et al., 2001) showed a mutation in the MYH11 gene, a deletion of 72 nucleotides within exon 28 (160745.0002). Zhu et al. (2006) suggested that the position of the mutations observed in the French and American kindreds may affect the coiled-coil structure of smooth muscle myosin heavy chain (SM-MHC) and the assembly of myosin thick filaments. Abnormal immunologic recognition of SM-MHC and the colocalization of wildtype and mutant rod proteins in smooth muscle cells in conjunction with differences in their coimmunoprecipitation capacities strongly suggested a dominant-negative effect of the mutations.
The ascending aorta is placed under major mechanical stress during each cardiac cycle. Khau Van Kien et al. (2005) showed in the French kindred that individuals bearing the disease haplotype showed altered aortic stiffness parameters: notably, aortic compliance, which serves as an early marker of the disease. Zhu et al. (2006) extended this study to 49-first degree relatives, showing that aortic diameter was generally similar in those with and without the mutation, but that the carriers of the mutation had a lower aortic compliance (66% decrease) and a higher pulse wave velocity (73% increase; both p less than 0.001). Young asymptomatic mutation carriers already had aortic indices similar to those of symptomatic mutation carriers and significantly different from those of normal relatives of the same age. Thus, Zhu et al. (2006) concluded that MYH11 heterozygous mutation leads to an early and severe decrease in the elasticity of the aortic wall consistent with the role of smooth muscle cells in maintaining the mechanical properties of the thoracic aorta.
Alhopuro et al. (2008) identified somatic mutations in the MYH11 gene in 56 (56%) of 101 samples of colorectal cancer (114500) tissue showing microsatellite instability. All mutations were within a mononucleotide repeat of 8 cytosines (C8) in the last exon of the MYH11 SM2 isoform, which is susceptible to mutations under microsatellite instability, and were predicted to lead to a frameshift and elongation of the protein. All mutations were found within epithelial cells. Analysis of microsatellite stable tumors identified 2 somatic mutations in the same tumor that were not in the C8 repeat. Functional expression studies of the mutant proteins showed unregulated actin-activated motor activity.
Pannu et al. (2007) sequenced the MYH11 gene in 3 probands from 3 TAAD families in which 1 or more members had patent ductus arteriosus (PDA) and in 93 probands from unrelated TAAD families without PDA, and identified mutations in 2 TAAD/PDA families: family TAA027 had 2 closely linked missense mutations (L1264P, 160745.0003 and R1275L, 160745.0004) and family TAA069 had a different missense mutation (R712Q, 160745.0005). Analysis of aortic sections and explanted smooth muscle cells from mutation-positive individuals from both families revealed upregulation of insulin-like growth factor-1 (IGF1; 147440) but no increase in transforming growth factor-beta (TGFB; 190180) or downstream targets. Enhanced expression levels of angiotensin-converting enzyme (ACE; 106180) and markers of angiotensin II (106150) vascular inflammation, e.g., macrophage inflammatory proteins 1-alpha (MIP1A; 182283) and 1-beta (MIP1B; 182284), were also found.
Visceral Myopathy 2
In 7 affected members of a 3-generation family segregating autosomal dominant visceral myopathy-2 (VSCM2; 619350), Dong et al. (2019) identified heterozygosity for a 1-bp deletion in the MYH11 gene (160745.0011). The variant was not found in unaffected family members and was present at a rare minor allele frequency in the gnomAD database (0.0000653).
In a father and 4 children (family 1) with predominantly esophageal symptoms due to gastrointestinal smooth muscle dysmotility, Gilbert et al. (2020) identified heterozygosity for a 2-bp insertion in the MYH11 gene (160745.0012) that was not found in 2 unaffected family members. In the proband from a 4-generation family (family 2) with a chronic intestinal motility disorder, they identified heterozygosity for the previously identified 1-bp deletion in MYH11 (160745.0011). Gilbert et al. (2020) noted that both the insertion and deletion are located within a polycytosine tract in the last coding exon of SM2 isoforms of MYH11 and do not affect the SM1 isoforms; thus the phenotype is isoform-specific.
Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome 2
In an Algerian infant who died with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS2; 619351), Gauthier et al. (2015) identified homozygosity for a nonsense mutation in the MYH11 gene (K1200X; 160745.0006). His unaffected consanguineous parents were heterozygous for the mutation, which was not found in ethnically matched controls or public variant databases. The authors noted that the proband's parents and extended family were not known to have thoracic aneurysms or dissections, but were not available for echocardiographic studies.
In a male infant who died at 18 months of age with MMIHS, Yetman and Starr (2018) identified compound heterozygosity for frameshift mutations in the MYH11 gene (160745.0007 and 160745.0008). His unaffected parents, who were each heterozygous for one of the mutations, had normal echocardiograms and showed no evidence of mydriasis or other smooth muscle dysfunction.
In a Chinese family in which 3 male fetuses had progressive megacystis and oligohydramnios on prenatal ultrasound, Wang et al. (2019) identified compound heterozygosity for a missense mutation (R684H; 160745.0009) and a deletion/insertion (160745.0010) in the MYH11 gene. The unaffected parents, who showed no evidence of vascular smooth muscle disease, were each heterozygous for one of the mutations.
Maddirevula et al. (2019) searched their database of 799 research and 1,750 clinical exomes for homozygous variants that would otherwise qualify for pathogenic or likely pathogenic classification according to ACMG guidelines except that the involved genes had only tentative links to disease. They identified homozygosity for a splicing mutation in the MYH11 gene (c.1033+1G-A) in a fetus (17-807) with massively dilated bladder with echogenic kidney and bilateral hydronephrosis. This was the fifth pregnancy in a 27-year-old mother who had previously experienced a spontaneous abortion at 2 months with her first pregnancy, terminated the second due to massively dilated bladder, had intrauterine fetal demise at 7 months with the third pregnancy, and terminated the fourth pregnancy at 15 weeks due to Potter sequence. The mutation was not found in the Saudi Human Genome Program or gnomAD databases.
Associations Pending Confirmation
Among 32 patients with Peutz-Jeghers syndrome (PJS; 175200) and 66 patients with unspecified hamartomatous polyposis, Alhopuro et al. (2008) identified 1 PJS patient with a heterozygous germline 1-bp insertion in the C8 repeat of the MYH11 gene. This mutation was also identified in the somatic state in a colorectal tumor from an unrelated patient, but not in 1,015 controls. The patient had a cystic astrocytoma at age 13 years. At age 23 years, he developed intussusception and was diagnosed with typical PJS. His unaffected father also carried the mutation. There was no family history of the disorder, and the patient did not have a STK11 (602216) mutation. Based on a zebrafish phenotype (see ANIMAL MODEL), Alhopuro et al. (2008) postulated autosomal recessive inheritance and the presence of a second unidentified MYH11 mutation.
Major changes in the structure and composition of the ductus arteriosus occur before and after delivery, and these changes require smooth muscle cells to migrate, proliferate, differentiate, and contract (Slomp et al., 1997). Homozygous MYH11 -/- mice deficient in SM-MHC have delay in closure of the ductus arteriosus (Morano et al., 2000). The SM-MHC-deficient mice also presented a giant thin-walled bladder and abnormal intestinal movement. No symptoms of this type were observed in the affected members with AAT4.
The autosomal recessive Zebrafish meltdown (mlt) lethal phenotype is characterized by cystic expansion of the posterior intestine as a result of stromal invasion of nontransformed epithelial cells. Using positional cloning, Wallace et al. (2005) determined that the mlt phenotype resulted from a mutation in the Myh11 gene that causes constitutive activation of the Myh11 ATPase and disruption of smooth muscle cells surrounding the posterior intestine. The findings implicated an essential role for smooth muscle signaling in the maintenance of epithelial architecture.
In the French 'Bourgogne' kindred described by Khau Van Kien et al. (2004) with familial thoracic aortic aneurysm/dissection with patent ductus arteriosus mapping to chromosome 16p12.2-p13.13 (AAT4; 132900), Zhu et al. (2006) detected 2 heterozygous mutations affecting the same allele of the MYH11 gene: a substitution at the splice donor site of intron 32 (IVS32+1G-T), and a missense mutation in exon 37 (5361G-A) resulting in a charged amino acid, arginine, being replaced by an uncharged amino acid, glutamine (R1758Q). The corresponding cDNA demonstrated that exon 32 was missing, resulting in an in-frame deletion of 71 amino acids (L1456_N1526del) in the C-terminal region of the smooth muscle myosin heavy chain (SM-MHC).
In the American kindred with AAT4 (132900) reported by Glancy et al. (2001), Zhu et al. (2006) detected a heterozygous 72-nucleotide deletion within exon 28 of the MYH11 gene (3810_3881del) that was not detected in 340 normal chromosomes. This in-frame deletion corresponds to the loss of 24 amino acids (R1241_L1264del) in the C-terminal region of the SM-MHC.
In affected members of a 3-generation family (TAA027) with aortic aneurysm and patent ductus arteriosus (AAT4; 132900), Pannu et al. (2007) identified 2 closely linked missense mutations in the MYH11 gene: a c.3791T-C transition (c.3791T-C, NM_002474), resulting in a leu1264-to-pro (L1264P) substitution, and a c.3824G-T transversion (c.3824G-T, NM_002474), resulting in an arg1275-to-leu (R1275L) substitution. Both mutations are in the coiled-coil domain. Cosegregation of the 2 alterations suggested that the mutations are in linkage disequilibrium.
In affected members of a family (TAA069) with aortic aneurysm and patent ductus arteriosus (AAT4; 132900), Pannu et al. (2007) identified a c.2153C-T transition (c.2153C-T, NM_002474) in the MYH11 gene, resulting in an arg712-to-gln (R712Q) substitution in the ATPase head region. The proband's affected father also had acute myocardial infarction (MI) at age 47 years, and a mutation-positive brother died of MI at age 43 years.
In an Algerian infant who died with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS2; 619351), Gauthier et al. (2015) identified homozygosity for a c.3598A-T transversion (c.3598A-T, NM_022844) in exon 27 of the MYH11 gene, resulting in a lys1200-to-ter (K1200X) substitution within the C-terminal coiled-coil domain. His unaffected consanguineous parents were heterozygous for the mutation, which was not found in 323 ethnically matched controls or in the dbSNP, 1000 Genomes Project, or EVS databases.
In a male infant who died at age 18 months with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS2; 619351), Yetman and Starr (2018) identified compound heterozygosity for 2 frameshift mutations in the MYH11 gene: a 2-bp deletion (c.2809_2810del) in exon 22, and a 49-bp deletion (c.3422_3470del; 160745.0008) in exon 26, both predicted to result in premature termination codons (Arg937GlyfsTer7 and Lys1141ThrfsTer20, respectively). Additional features in this patient included congenital mydriasis and sensorineural hearing loss, lung disease, pulmonary hypertension, and mild aortic dilation. His unaffected parents, who were each heterozygous for one of the mutations, had normal echocardiograms and showed no evidence of mydriasis or other smooth muscle dysfunction. The authors stated that the 2-bp deletion had been reported in 0.0001% of the population, whereas the 49-bp deletion was novel.
For discussion of the 49-bp deletion (c.3422_3470del) in exon 26 of the MYH11 gene, causing a frameshift predicted to result in premature termination (Lys1141ThrfsTer20), that was found in compound heterozygous state in a male infant with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS2; 619351) by Yetman and Starr (2018), see 160745.0007.
In 2 male fetuses from a Chinese family with progressive megacystis and oligohydramnios on prenatal ultrasound (MMIHS2; 619351), Wang et al. (2019) identified compound heterozygosity for 2 mutations in the MYH11 gene: a c.2051G-A transition (c.2051G-A, NM_001040114), resulting in an arg684-to-his (R684H) substitution at a highly conserved residue near a complex salt bridge domain, and a deletion/insertion (c.3540_3541delinsTT; 160745.0010), resulting in a change of glu1180-to-asp (E1180D) and gln1181-to-ter (Q1181X). The R684H variant was reported at a low frequency in the gnomAD database (1/245,930), whereas the deletion/insertion mutation was novel. The unaffected parents, who showed no evidence of vascular smooth muscle disease, were each heterozygous for one of the mutations. DNA was unavailable from a third similarly affected fetus in this family. Western blot of umbilical cord tissue from the proband showed markedly decreased MYH11 protein compared to control tissue.
For discussion of the deletion/insertion mutation (c.3540_3541delinsTT, NM_001040114) in the MYH11 gene that was found in compound heterozygous state in 2 Chinese male fetuses with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS2; 619351) by Wang et al. (2019), see 160745.0009.
In 7 affected members of a 3-generation family (RQ6654) with visceral myopathy (VSCM2; 619350) manifesting as megacystis and chronic intestinal pseudoobstruction, Dong et al. (2019) identified heterozygosity for a 1-bp deletion (c.5819delC, NM_001040113) in the last exon of the MYH11 gene, 5 amino acids from the stop codon, causing a frameshift predicted to generate a new stop codon 91 bases away (Pro1940HisfsTer91). The mutation was not found in 3 unaffected family members. It was not present in the gnomAD database but was present at a rare minor allele frequency in the ExAC database (0.0000653).
In a 30-year-old woman of Mexican and Arab descent from a 4-generation family (family 2) with a chronic intestinal motility disorder, Gilbert et al. (2020) identified heterozygosity for the c.5819delC mutation in the MYH11 gene, located within a polycytosine tract in the last coding exon of the SM2 isoform. Other affected family members were unavailable for evaluation. The proband was also heterozygous for a L1555V missense mutation in MYH11 in a region that appeared to be tolerant to variation; the authors were not able to phase the deletion and missense variants, and stated that it was also possible that the variants occurred on the same allele. The missense L1555V variant was not present in gnomAD, but the authors noted that the database is skewed toward European ethnicities.
In a father and 4 children (family 1) with predominantly esophageal symptoms due to gastrointestinal smooth muscle dysmotility (VSCM2; 619350), Gilbert et al. (2020) identified heterozygosity for a 2-bp insertion (c.5819_5820insCA, NM_001040113), causing a frameshift resulting in a synonymous substitution at the sixth-to-last amino acid, followed by the addition of 90 unique amino acids before termination (Gln1941AsnfsTer91). The mutation segregated fully with disease in the family and was not found in the ExAC or gnomAD databases.
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