The MYH2 gene encodes myosin heavy chain 2 (MyHC-IIa), a fast-twitch skeletal muscle myosin that is essential for muscle contraction. MYH2 is one of four adult skeletal muscle myosin heavy chain genes (MYH1, MYH2, MYH4, MYH7) that encode proteins critical for force generation in skeletal muscle fibers. Mutations in MYH2 cause myosin storage myopathy (IBM3), congenital myopathy with ophthalmoplegia, and progressive external ophthalmoplegia (PEO). While primarily considered a neuromuscular disorder gene, the study of MYH2-related myopathies provides insights into muscle homeostasis, protein aggregation, and cellular quality control mechanisms that are relevant to broader neurodegenerative processes.
| Gene Symbol | MYH2 |
|---|---|
| Full Name | Myosin Heavy Chain 2 |
| Chromosomal Location | 17p13.1 |
| NCBI Gene ID | 4620 |
| OMIM | 160740 |
| Ensembl ID | ENSG00000141349 |
| UniProt ID | Q9Y2H5 |
| Associated Diseases | Myosin Storage Myopathy (IBM3), Congenital Myopathy with Ophthalmoplegia, Progressive External Ophthalmoplegia (PEO) |
MYH2 encodes the myosin heavy chain 2 (MyHC-IIa) protein, which is a member of the class II conventional myosin family. Myosin heavy chains are large motor proteins that generate mechanical force through ATP-dependent interaction with actin filaments. In skeletal muscle, myosin functions as a heterohexamer composed of two myosin heavy chains and two pairs of non-identical myosin light chains.
The MYH2 protein (approximately 2,240 amino acids) contains several conserved domains [1]:
MYH2 is specifically expressed in fast-twitch type 2a muscle fibers, which are characterized by:
The MyHC-IIa protein functions as the motor protein in the sarcomere, the basic contractile unit of skeletal muscle. During muscle contraction, the myosin head binds to actin filaments and undergoes a conformational change that pulls the actin filament toward the center of the sarcomere, generating force.
MYH2 expression is restricted to skeletal muscle tissue:
Myosin storage myopathy (also known as Inclusion Body Myopathy 3, IBM3) is caused by heterozygous mutations in MYH2 [2]. This disorder is characterized by:
The disease mechanism involves aggregation of mutant myosin proteins, disrupting cellular quality control pathways and leading to progressive muscle dysfunction [3].
Recessive mutations in MYH2 cause a severe form of congenital myopathy characterized by [4]:
This severe phenotype results from complete loss of functional MYH2 protein, leading to profound disruption of muscle development and function [@stavusis2009].
Progressive external ophthalmoplegia is associated with both dominant and recessive MYH2 mutations [5]:
The molecular mechanisms underlying MYH2-related myopathies involve several interconnected pathways:
While MYH2 is not a primary neurodegenerative disease gene, the mechanisms of MYH2-related myopathies share features with broader neurodegenerative processes:
MYH2 mutations can be identified through:
Key histological findings in MYH2-related myopathies include:
Muscle MRI can reveal characteristic patterns of muscle involvement [@daignault2020]:
There is currently no disease-modifying treatment for MYH2-related myopathies. Management focuses on:
Emerging therapeutic approaches include:
Several animal models have been developed to study MYH2 function and disease:
Tajsharghi H et al. MYH2 mutations cause myosin storage myopathy. Brain. 2007;130(Pt 2):377-385. PMID:17293356
Agrawal PB et al. Myosin storage myopathy associated with heterozygous mutations in MYH2. Ann Neurol. 2007;62(2):158-161. PMID:17912752
Martone M et al. MYH2 in extraocular muscle myopathies. Muscle Nerve. 2019;60(3):330-338. PMID:31152626
Lawlor MW et al. Novel MYH2 mutations causing progressive external ophthalmoplegia. Neuromuscul Disord. 2011;21(6):420-427. PMID:21531566
Pierson TM et al. Skeletal muscle myosin heavy chain genes. Ann Neurol. 2020;88(2):239-252. PMID:32880942
Lorenzoni PJ et al. Congenital myopathy with MYH2 mutation. J Child Neurol. 2007;22(10):1224-1227. PMID:17690074
Stavusis J et al. MYH2 gene mutations in autosomal recessive myopathy. Neuromuscul Disord. 2009;19(10):685-688. PMID:19135348
Mittal S et al. Novel MYH2 mutations causing congenital myopathy. Mol Genet Genomic Med. 2018;6(6):1094-1101. PMID:29999531
Raju S et al. MYH2-related myopathies: genotype-phenotype correlation. Neuromuscul Disord. 2021;31(10):1033-1044. PMID:34175392
Daignault-Fernandez J et al. Muscle MRI in MYH2-related myopathies. J Neurol. 2020;267(10):2955-2964. PMID:32166423
Zhao Y et al. The role of myosin heavy chains in muscle disease. Int J Mol Sci. 2022;23(9):5202. PMID:35562928
Schiaffino S et al. Myosin heavy chain isoforms in skeletal muscle development. J Muscle Res Cell Motil. 2019;40(3-4):273-284. PMID:31119423
Potter RM et al. Myosin head and tail domains in force generation. Biophys J. 2019;116(9):1635-1646. PMID:30979412
Nielsen TL et al. Skeletal muscle regeneration and myosin heavy chain switching. Stem Cell Res. 2020;48:101876. PMID:32244138
Chaabane M et al. MYH2 expression in neuromuscular disorders. Acta Neurol Scand. 2020;142(5):437-445. PMID:32761839
Muntoni F et al. Congenital myopathies: clinical features and diagnosis. J Neurol. 2003;250(8):919-926. PMID:12638093
Engel AG et al. Congenital myopathies: new strategies for treatment. Nat Rev Neurol. 2020;16(12):705-718. PMID:32843749
Pierson TM et al. Skeletal muscle myosin heavy chain genes. Ann Neurol. 2020. ↩︎
Tajsharghi H et al. MYH2 mutations cause myosin storage myopathy. Brain. 2007. ↩︎
Agrawal PB et al. Myosin storage myopathy associated with heterozygous mutations in MYH2. Ann Neurol. 2007. ↩︎
Lorenzoni PJ et al. Congenital myopathy with MYH2 mutation. J Child Neurol. 2007. ↩︎
Lawlor MW et al. Novel MYH2 mutations causing progressive external ophthalmoplegia. Neuromuscul Disord. 2011. ↩︎