An α-Tropomyosin mutation alters dimer preference in nemaline myopathy

被引:44
作者
Corbett, MA
Akkari, PA
Domazetovska, A
Cooper, ST
North, KN
Laing, NG
Gunning, PW
Hardeman, EC
机构
[1] Childrens Med Res Inst, Muscle Dev Unit, Wentworthville, NSW 2145, Australia
[2] Univ Western Australia, Western Australian Inst Med Res, QEII Med Ctr, Ctr Neuromuscular & Neurol Disorders, Nedlands, WA 6009, Australia
[3] Univ Western Australia, Western Australian Inst Med Res, QEII Med Ctr, Med Res Ctr, Nedlands, WA 6009, Australia
关键词
D O I
10.1002/ana.20305
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Nemaline myopathy is a human neuromuscular disorder associated with muscle weakness, Z-line accumulations (rods), and myofibrillar disorganization. Disease-causing mutations have been identified in genes encoding muscle thin filament proteins: actin, nebulin, slow troponin T, betaTropomyosin, anti alphaTropomyosin(slow). Skeletal muscle expresses three tropomyosin (Tm) isoforms from separate genes: alphaTm(fast)(alphaTm, TPM1), betaTm (TPM2), and alphaTm(slow) (gammaTm, TPM3). In this article, we show that the level of betaTm, but not alphaTm(fast) protein, is reduced in human patients with mutations in alphaTm(slow) and in a transgenic mouse model of alphaTm(slow)(Met9Arg) nemaline myopathy. A postnatal time course of Tm expression in muscles of the mice indicated that the onset of alphaTm(slow)(Met9Arg) expression coincides with the decline of betaTm. Reduction of betaTm levels is independent of the degree of pathology (rods) within a muscle and is detected before the onset of muscle weakness. Thus, reduction in the level of betaTm represents an early clinical diagnostic marker for alphaTm(slow)-based mutations. Examinations of tropomyosin dimer formation using either recombinant proteins or sarcomeric extracts show that the mutation reduces the formation of the preferred alpha/beta heterodimer. We suggest this perturbation of tropomyosin isoform levels and dimer preference alters sarcomeric thin filament dynamics and contributes to muscle weakness in nemaline myopathy.
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页码:42 / 49
页数:8
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