Mutation of the slow myosin heavy chain rod domain underlies hyaline body myopathy
Abstract
Objective: To identify the gene and specific mutation underlying hyaline body myopathy in the family studied.
Methods: A microsatellite-based whole genome scan was performed. Linkage analysis assumed autosomal dominant inheritance and equal allele frequencies. A candidate gene approach within the linked interval and direct sequencing were used for mutation detection.
Results: Initial analysis indicated a maximum lod score of 3.01 at D14S1280. High-density mapping surrounding the linked locus was performed. Multipoint analysis showed that the linked region with a maximum lod score of 3.01 extended from D14S742 to D14S608 with a peak non-parametric linkage (NPL) score of 3.75 at D14S608. The myosin heavy chain genes MYH6 and MYH7 map to the region between D14S742 and D14S1280. Sequence analysis of the coding regions of MYH7 revealed an A→T transversion at nucleotide position 25596 (M57965) resulting in a histidine-to-leucine amino acid change at residue 1904 (H1904L).
Conclusion: Pathogenicity of the MYH7 H1904L mutation most likely results from disruption of myosin heavy chain assembly or stability of the sarcomeric protein. The MYH7 tail domain mutation results in an inclusion body myopathy with an apparent absence of hypertrophic cardiomyopathy usually associated with mutations of this gene.
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Received: November 3, 2003
Accepted: January 7, 2004
Published online: May 10, 2004
Published in print: May 11, 2004
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We previoulsy described [2] another heterozygous missense mutation, R1845W, in the distal rod region of MyHC I, (MYH7) in a sporadic case as well as in a family with autosomal dominant inheritance. Since we found that the disease was caused by mutation in MYH7 and its main morphological characteristic is large subsarcolemmal accumulation of myosin in type 1 muscle fibers, we proposed the name "Myosin Storage Myopathy" (OMIM# 608358) for this entity, which previously has been ascribed various terms in the literature including "hyaline body" myopathy. Interestingly, two additional sporadic cases with identical mutations as in ours are referred to in the recent 3rd edition of Myology. [3]
Both mutations described are located at an "f " position of the heptad repeat of the coiled-coil structure of the MyHC rod that forms the backbone of the thick filaments of the sarcomeres. This confirms our hypothesis that "Myosin Storage Myopathy" is caused by defective assembly of the thick filaments, since residues at "f" position of the coiled-coils may interact with other myosin dimers or with other proteins that are essential for the assembly of the thick filaments. This is also of interest in relation to familial hypertrophic cardiomyopathy, which in many cases is caused by mutations in MYH7 and thus may be allelic to "Myosin Storage Myopathy". Since patients with Myosin Storage Myopathy do not show cardiomyopathy there may be MyHC-interacting proteins, which are specific for skeletal muscle, and interact with the distal rod region of the MyHC.
In the article by Bohlega et al, the numbering of the mutated residue conflicts with the base substitution that was presented. According to Swiss-Prot (http://ca.expasy.org/), the mutated amino acid sequence number is H1901 and not H1904. The residue 1904 in human MyHC I is not at an "f "position in the heptad repeat sequence, whereas the amino acid at position 1901 is.
References
1. Bohlega S, Abu-Amero SN, Wakil SM, et al. Mutation of the slow myosin heavy chain rod domain underlies hyaline body myopathy. Neurology 2004;62:1518-1521.
2. Tajsharghi H, Thornell LE, Lindberg C, Lindvall B, Henriksson KG, Oldfors A. Myosin storage myopathy associated with a heterozygous missense mutation in MYH7. Ann Neurol 2003;54:494-500.
3. North K. Congenital myopathies. In: Engel AG, Franzini- Armstrong C, editors. Myology. Basic and clinical. 3rd ed. New York: McGraw-Hill; 2004. p. 1473-1533.
We thank Oldfors et al for their comments. We previously described a heterozygous mutation (an A to T transversion at nucleotide position 25596;M57965) resulting in a histidine to leucine amino acid change at residue 1904 (H1904L) in all affected members of a family with autosomal dominant hyaline body myopathy. [1] Numbering was based upon definition of an Assembly Competent Domain (residues 1874 to 1902). [4]
The H1904L mutation was adjacent to and not encompassed within this region. This same mutation would be cited as H1901L based upon Swiss-Prot (http://ca.expasy.org/). Aside from what numbering was chosen, the mutation does occupy an "f" position in the heptad repeat of the coiled-coil or tail domain of MYH7. [5] This is interesting in light of another mutation of this domain occuring in the "f" position and producing essentially the same phenotype. [2-3]
In contrast, mutations of the tail domain in other positions of the heptad have been associated with familial hypertrophic cardiomyopathy [5]indicating allelic heterogeneity at this locus.
References
1. Bohlega S, Abu-Amero SN, Wakil SM, et al. Mutation of the slow myosin heavy chain rod domain underlies hyaline body myopathy. Neurology 2004;62:1518-1521.
2. Tajsharghi H, Thornell LE, Lindberg C, Lindvall B, Henriksson KG, Oldfors A. Myosin storage myopathy associated with a heterozygous missense mutation in MYH7. Ann Neurol 2003;54:494-500.
3. North K. Congenital myopathies. In: Engel AG, Franzini- Armstrong C, editors. Myology. Basic and clinical. 3rd ed. New York: McGraw-Hill; 2004. p. 1473-1533.
4. Sohn RL, Vikstrom KL, Strauss M, Cohen C, Szent-Gyorgyi AG, Leinwand LA. A 29 residue region of the sarcomeric myosin rod is necessary for filament formation. J Mol Biol 1997; 266: 317-330.
5) Blair E, Redwood C, de Jesus Oliveira M, et al. Mutations of the light meromyosin domain of the beta-myosin heavy chain rod in hypertrophic cardiomyopathy. Circ Res 2002; 90: 263-269.