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An αtropomyosin mutation alters dimer preference in nemaline myopathy
Author(s) -
Corbett Mark A.,
Anthony Akkari P.,
Domazetovska Ana,
Cooper Sandra T.,
North Kathryn N.,
Laing Nigel G.,
Gunning Peter W.,
Hardeman Edna C.
Publication year - 2005
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.20305
Subject(s) - nemaline myopathy , tropomyosin , nebulin , muscle weakness , myopathy , congenital myopathy , gene isoform , skeletal muscle , actin , biology , chemistry , genetics , medicine , microbiology and biotechnology , anatomy , myocyte , gene , sarcomere , muscle biopsy , titin , biopsy
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, βTropomyosin, and αTropomyosin slow . Skeletal muscle expresses three tropomyosin (Tm) isoforms from separate genes: αTm fast (α Tm, TPM1 ), βTm ( TPM2 ), and αTm slow (γ Tm, TPM3 ). In this article, we show that the level of βTm, but not αTm fast protein, is reduced in human patients with mutations in αTm slow and in a transgenic mouse model of αTm slow (Met9Arg) nemaline myopathy. A postnatal time course of Tm expression in muscles of the mice indicated that the onset of αTm slow (Met9Arg) expression coincides with the decline of βTm. Reduction of βTm 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 βTm represents an early clinical diagnostic marker for αTm 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 α/β 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. Ann Neurol 2004