Disease relevance of MYH2

• BACKGROUND: The authors recently described a new autosomal dominant myopathy (OMIM 605637 inclusion body myopathy 3) associated with a missense mutation in the myosin heavy chain (MyHC) IIa gene (MyHC IIa, Human Gene Map [HGM] locus MYH2) [1].
• The MyHC IIa E706K mutation is associated with congenital joint contractures, early-onset muscle weakness, and progressive course with moderate to severe muscle weakness later in life [2].

High impact information on MYH2

• Autosomal dominant myopathy: missense mutation (Glu-706 --> Lys) in the myosin heavy chain IIa gene [3].
• The common regions of loss of heterozygosity on chromosomes 3, 13, and 17 reside between D3S2 (3p14-p21) and ERBA beta (3p22-p24.1), between D13S1 (13q12) and D13S2 (13q22), and distal to MYH2 (17p13.1), respectively [4].
• We demonstrate that S100A4 mutants that are defective in either their ability to dimerize or in calcium binding are unable to interact with myosin heavy chain IIA [5].
• PstI RFLP at the MYH2 locus on chromosome 17 [6].
• The consistent expression of MyHC IIa in muscle fibers with rimmed vacuoles indicates that the breakdown of sarcomeric proteins is a key element in the pathogenesis of rimmed vacuoles of s-IBM type [1].

Associations of MYH2 with chemical compounds

• Supporting these observations, IL8- or cell-permeable cGMP analog-induced formation of cADP-ribose, increase in [Ca(2+)](i), and migration of LAK cells were inhibited by treatment with the MHCIIA inhibitor blebbistatin [7].

Biological context of MYH2

• In addition, we analyzed the extent and distribution of nucleotide variation in MYH2 in 50 blood donors, who served as controls, by the complete sequencing of all 38 exons comprising the coding region [8].

Anatomical context of MYH2

• Segregation information data for an inferred recombinant offspring indicated that the CMT1A locus is probably proximal to MYH2, the locus encoding adult skeletal muscle myosin heavy polypeptide 2, which maps to 17p13 [9].
• We recently described a new autosomal dominant myopathy (OMIM #605637) associated with a missense mutation in the myosin heavy chain (MyHC) IIa gene ( MYH2), which encodes for the fast myosin isoform that is expressed in type 2A muscle fibers [10].
• Here we show that S100A4 localizes to lamellipodia structures in a migrating breast cancer-derived cell line and colocalizes with a known S100A4-interacting protein, myosin heavy chain IIA, at the leading edge [5].
• MyHC IIa expression was a consistent finding in muscle fibers with rimmed vacuoles [1].
• Our results provide evidence that the pathogenesis of the MyHC IIa E706K myopathy involves defective function of the mutated myosin as well as alterations in the structural integrity of all muscle cells irrespective of MyHC isoform expression [11].

Other interactions of MYH2

• Endurance training in a group of affected patients caused a shift in the expression of myosin from fast (IIx) to slow (I) isoforms but no reduction in the expression of MyHC IIa [12].
• This holds also true for myosin heavy chain IIa, but human myosin heavy chain IIb is slower than rodent myosin heavy chain IIb [13].
• Mutations in the non-muscle myosin heavy chain IIA gene (MYH9) are responsible for May-Hegglin anomaly, Sebastian, Fechtner and Epstein syndromes [14].

Analytical, diagnostic and therapeutic context of MYH2

• METHODS: The expression of MyHC IIa in nine muscle specimens from six individuals carrying the mutation was analyzed by immunohistochemistry, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and a new reverse transcriptase--PCR method to measure the relative abundance of the various MyHC transcripts [1].

References