Incidental Mutation 'G5030:Myh11'

• ID: 487
• Institutional Source: Beutler Lab
• Gene Symbol: Myh11
• Ensembl Gene: ENSMUSG00000018830
• Gene Name: myosin, heavy polypeptide 11, smooth muscle
• Synonyms: smMHC, SM1, SM2
• Essential gene?: Essential (E-score: 1.000)
• Stock #: G5030 (G3) of strain 560
• Status: Validated
• Chromosome: 16
• Chromosomal Location: 14012392-14109227 bp(-) (GRCm39)
• Type of Mutation: missense
• DNA Base Change (assembly): T to C at 14068443 bp (GRCm39)
• Zygosity: Homozygous
• Amino Acid Change: Isoleucine to Methionine at position 192 (I192M)
• Ref Sequence: ENSEMBL: ENSMUSP00000155052
• Gene Model: predicted gene model for transcript(s): [ENSMUST00000090287] [ENSMUST00000230397] [ENSMUST00000231567]
• AlphaFold: no structure available at present
• Predicted Effect: probably damaging; Transcript: ENSMUST00000090287; AA Change: I192M; PolyPhen 2 Score 0.992 (Sensitivity: 0.70; Specificity: 0.97)
• SMART Domains: Protein: ENSMUSP00000087756; Gene: ENSMUSG00000018830; AA Change: I192M

Domain	Start	End	E-Value	Type
Pfam:Myosin_N	33	73	1e-15	PFAM
MYSc	79	784	N/A	SMART
IQ	785	807	1.09e-2	SMART
Pfam:Myosin_tail_1	848	1928	N/A	PFAM

• Predicted Effect: probably damaging; Transcript: ENSMUST00000230397; AA Change: I192M; PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
• Predicted Effect: noncoding transcript; Transcript: ENSMUST00000230643
• Predicted Effect: probably damaging; Transcript: ENSMUST00000231567; AA Change: I192M; PolyPhen 2 Score 0.995 (Sensitivity: 0.68; Specificity: 0.97)
• Meta Mutation Damage Score: 0.6467
• Coding Region Coverage:
  • 1x: 81.1%
  • 3x: 60.2%
• Het Detection Efficiency: 35.6%
• Validation Efficiency: 87% (206/237)
• MGI Phenotype: FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene is a smooth muscle myosin belonging to the myosin heavy chain family. The gene product is a subunit of a hexameric protein that consists of two heavy chain subunits and two pairs of non-identical light chain subunits. It functions as a major contractile protein, converting chemical energy into mechanical energy through the hydrolysis of ATP. The gene encoding a human ortholog of rat NUDE1 is transcribed from the reverse strand of this gene, and its 3' end overlaps with that of the latter. The pericentric inversion of chromosome 16 [inv(16)(p13q22)] produces a chimeric transcript that encodes a protein consisting of the first 165 residues from the N terminus of core-binding factor beta in a fusion with the C-terminal portion of the smooth muscle myosin heavy chain. This chromosomal rearrangement is associated with acute myeloid leukemia of the M4Eo subtype. Alternative splicing generates isoforms that are differentially expressed, with ratios changing during muscle cell maturation. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008] ; PHENOTYPE: Homozygous null mice have impaired smooth muscle contractility. They are incapable of urinating, exhibit dilative cardiomyopathy, are growth retarded, and die within 3 days of birth. [provided by MGI curators]
• Allele List at MGI:

  All alleles(4) : Targeted, knock-out(4)

• Posted On: 2010-10-27

Nature of Mutation

DNA sequencing using the SOLiD technique identified an A to G transition at position 725 of the Myh11 transcript using Genbank record NM_013607. Three transcripts of the Myh11 gene are displayed on Ensembl. The mutated nucleotide causes an isoleucine to methionine substitution at amino acid 192 of the encoded protein. The mutation has been confirmed by DNA sequencing using the Sanger method (Figure 1).

Protein Function and Prediction

The Myh11 gene encodes a 1972 amino acid member of the myosin family. Two isoforms are produced by alternative splicing. Myosins are actin-based motor molecules with ATPase activity.  Muscle contraction is caused by sliding between the thick and thin filaments of the myofibril. Myosin is a major component of thick filaments and exists as a hexamer of 2 heavy chains, 2 alkali light chains, and 2 regulatory light chains. The heavy chain (like MYH11) can be subdivided into the N-terminal globular head and the C-terminal coiled-coil rod-like tail, although some forms have a globular region in their C-terminal. There are many cell-specific isoforms of myosin heavy chains. MYH11 is expressed specifically in smooth muscle. The protein contains an EF-hand protein-binding IQ domain at residues 786-815, the N-terminal globular head at residues 1-785, and a C-terminal myosin tail at residues 1935-1972. Actin binding regions occur at amino acids 661-683 and 762-776 (Uniprot O08638). Homozygous null mice have impaired smooth muscle contractility. They are incapable of urinating, exhibit dilative cardiomyopathy, are growth retarded, and die within 3 days of birth. In humans, heterozygous mutations of MYH11 cause familial thoracic aortic aneurysm/dissection with patent ductus arteriosus (AAT4; OMIM 132900). In addition, somatic mutations have been identified in colorectal cancer.

The I192M change is located in the globular region, and is predicted to be possibly damaging by the PolyPhen program.