Malignant Hypertrophic Cardiomyopathy Caused by the Arg723Gly Mutation in β -Myosin Heavy Chain Gene

Enjuto, Montserrat; Francino, Antonio; Navarro-López, F; Viles, Dolors; Pare, J. C. rlos; Ballesta, Antonio M.

doi:10.1006/jmcc.2000.1260

Cited by 48 publications

(39 citation statements)

References 16 publications

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“…A whole cluster of mutations is located in the converter domain (14), with the substitutions Arg-723 3 Gly and Gly-716 3 Arg also resulting in a malignant phenotype (16,45). These two substitutions are also close to the first turns of the long ␣-helix.…”

Section: Relation To Other Studies On Mutations In the Converter Domainmentioning

confidence: 99%

Mutation of the myosin converter domain alters cross-bridge elasticity

Köhler

Winkler²,

Schulte³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Elastic distortion of a structural element of the actomyosin complex is fundamental to the ability of myosin to generate motile forces. An elastic element allows strain to develop within the actomyosin complex (cross-bridge) before movement. Relief of this strain then drives filament sliding, or more generally, movement of a cargo. Even with the known crystal structure of the myosin head, however, the structural element of the actomyosin complex in which elastic distortion occurs remained unclear. To assign functional relevance to various structural elements of the myosin head, e.g., to identify the elastic element within the cross-bridge, we studied mechanical properties of muscle fibers from patients with familial hypertrophic cardiomyopathy with point mutations in the head domain of the ␤-myosin heavy chain. We found that the Arg-719 3 Trp (Arg719Trp) mutation, which is located in the converter domain of the myosin head fragment, causes an increase in force generation and fiber stiffness under isometric conditions by 48 -59%. Under rigor and relaxing conditions, fiber stiffness was 45-47% higher than in control fibers. Yet, kinetics of active cross-bridge cycling were unchanged. These findings, especially the increase in fiber stiffness under rigor conditions, indicate that cross-bridges with the Arg719Trp mutation are more resistant to elastic distortion. The data presented here strongly suggest that the converter domain that forms the junction between the catalytic and the light-chain-binding domain of the myosin head is not only essential for elastic distortion of the cross-bridge, but that the main elastic distortion may even occur within the converter domain itself. It is widely accepted that active force and movement generated by muscle fibers result from structural changes in the head domain of the myosin molecule (the cross-bridge) while it is attached to the actin filament. These changes are thought to involve a tilting of the light-chain-binding domain of the myosin head relative to its catalytic domain (1-7). As a result of such structural changes distortion of an elastic element within the actin-attached myosin head allows strain to develop before movement (8). Relief of this strain drives sliding of actin filaments past the myosin filaments, or alternatively, if filament sliding is prevented, active force is generated because of continued strain of the elastic element. Despite the central significance of this concept, however, it remained unclear which part of the actomyosin complex represents the elastic element-i.e., the element that experiences the main elastic distortion while other parts act more like rigid bodies. Neither the known crystal structures of the myosin head nor cryo-electron microscopy with reconstruction of the actomyosin complex have resolved this question. Some authors considered elastic bending of the long, light-chain-binding ␣-helix an obvious candidate (4, 9, 10). The actin-myosin interface (11) or the junction between the lightchain domain and the catalytic domain of the...

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Section: Relation To Other Studies On Mutations In the Converter Domainmentioning

confidence: 99%

Mutation of the myosin converter domain alters cross-bridge elasticity

Köhler

Winkler²,

Schulte³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…He was successfully transplanted at the age of 59 yr. His exercise capacity at the time of biopsy (pretransplant) was restricted [New York Heart Association (NYHA) functional class IV]. The brother of this patient received an implantable cardioverter-defibrillator, and two other members of the same family died suddenly (9). The patient who carries the ␤-MHC mutation Arg719Trp is a female member of a British family.…”

Section: Methodsmentioning

confidence: 99%

“…Soleus muscle biopsies were obtained from three patients who were previously clinically and genetically characterized as HCM patients caused by mutations in the converter domain of ␤-MHC. One patient is the member of a HCM family from Barcelona who carries the ␤-MHC mutation Arg723Gly (9). Clinical details of this patient, patient II-2, from family 26 in Enjuto et al (9) have been published.…”

Section: Methodsmentioning

confidence: 99%

“…One patient is the member of a HCM family from Barcelona who carries the ␤-MHC mutation Arg723Gly (9). Clinical details of this patient, patient II-2, from family 26 in Enjuto et al (9) have been published. He was successfully transplanted at the age of 59 yr. His exercise capacity at the time of biopsy (pretransplant) was restricted [New York Heart Association (NYHA) functional class IV].…”

Section: Methodsmentioning

confidence: 99%

“…Muscle fibers from three patients carrying different point mutations were studied: Arg723Gly [Barcelona mutation (9)], Arg719Trp (1), and Ile736Thr (3). With the use of our specifically developed method for long-term preservation of fully functional skinned fibers, it was possible to study an adequate number of muscle fibers from each individual patient.…”

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confidence: 99%

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