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1.
Brain ; 126(Pt 7): 1545-51, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12805120

ABSTRACT

Nemaline myopathy is a congenital neuromuscular disorder characterized by muscle weakness and the presence of nemaline rods. Five genes have now been associated with nemaline myopathy: alpha-tropomyosin-3 (TPM3), alpha-actin (ACTA1), nebulin (NEB), beta-tropomysin (TPM2) and troponin T (TNNT1). In addition, mutations in the ryanodine receptor gene (RYR1) have been associated with core-rod myopathy. Here we report linkage in two unrelated families, with a variant of nemaline myopathy, with associated core-like lesions. The clinical phenotype consists of muscle weakness in addition to a peculiar kind of muscle slowness. A genome-wide scan revealed a locus for nemaline myopathy with core-like lesions on chromosome 15q21-q23 for both families. Combining the two families gave a two-point LOD score of 10.65 for D15S993. The alpha-tropomyosin-1 gene (TPM1) located within this region is the strongest candidate gene. However, no mutations were found in the protein-coding region of TPM1, although small deletions or mutations in an intron cannot be excluded. The critical region contains few other candidate genes coding for muscle proteins and several genes of unknown function, and has not yet been sequenced completely. The novel phenotype of nemaline myopathy in the two presented families corresponds to an also novel, as yet uncharacterized, genotype.


Subject(s)
Chromosomes, Human, Pair 15/genetics , Myopathies, Nemaline/genetics , Adolescent , Adult , Female , Genetic Linkage , Genotype , Haplotypes , Humans , Lod Score , Male , Microsatellite Repeats , Muscle, Skeletal/pathology , Myopathies, Nemaline/pathology , Pedigree , Phenotype , Tropomyosin/genetics
2.
Neuromuscul Disord ; 12(10): 952-7, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12467751

ABSTRACT

Skeletal muscle function was measured in anaesthetised transgenic mice having a mutation in the TPM3 gene (slow alpha-tropomyosin), a similar mutation as found in some patients with nemaline myopathy, and was compared with control muscles. Measurements of isometric and dynamic muscle performance were done with electrical nerve stimulation at physiological temperatures. No muscle weakness was found in the transgenic muscles when performance was measured at muscle optimum length. This was true not only with full activation but also at lower activation levels, indicating that calcium sensitivity was not affected at this length. Also, fatigability was not affected in these conditions. However, isometric force of the muscles with the mutation in TPM3 was lower at lengths below optimum, with more impairment at decreasing length. As the muscles are active over a large range of different muscle lengths during daily activities, this finding may explain, at least in part, the muscle weakness experienced by patients with nemaline myopathy.


Subject(s)
Isometric Contraction/physiology , Muscle Weakness/genetics , Muscle, Skeletal/physiopathology , Mutation , Tropomyosin/genetics , Animals , Electric Stimulation , Female , In Vitro Techniques , Isometric Contraction/genetics , Mice , Mice, Transgenic , Muscle Fatigue/genetics , Muscle Fatigue/physiology , Muscle Weakness/physiopathology
3.
J Muscle Res Cell Motil ; 23(1): 59-63, 2002.
Article in English | MEDLINE | ID: mdl-12363286

ABSTRACT

Changes in intracellular Ca2+-concentration play an important role in the excitation-contraction-relaxation cycle of skeletal muscle. In this review we describe various inheritable muscle diseases to highlight the role of Ca2+-regulatory mechanisms. Upon excitation the ryanodine receptor releases Ca2+ in the cytosol. During and after contraction the sarcoplasmic reticulum (SR) Ca2+ATPase (SERCA) pumps Ca2+ back in the SR resulting in relaxation. An abnormal change in the intracellular Ca2+-concentration results in defective muscle contraction and/or relaxation, which is the cause of various muscle diseases. Malignant hyperthermia (MH) and central core disease (CCD) are both caused by mutations in the ryanodine receptor but show different clinical phenotypes. In MH an acute increase of Ca2+ results in excessive muscle contraction causing rigidity, while in CCD a chronic rise of cytosolic Ca2+ is seen, leading to mitochondrial damage, disorganization of myofibrils and muscle weakness. In Brody disease and also in mitochondrial myopathies, SERCA functions sub optimal causing a prolonged physiological Ca2+-elevation leading to slowing of relaxation. Defective actin-myosin interactions, as in nemaline myopathy and also in mitochondrial myopathies due to ATP-shortage, cause Ca2+-hyposensitivity and slowness of contraction. Information of Ca2+-kinetics in these inherited muscular diseases improves our understanding of the role of calcium in the physiology and pathophysiology of the skeletal muscle cell.


Subject(s)
Calcium/metabolism , Muscular Diseases/metabolism , Animals , Humans , Muscle Contraction/physiology , Muscle Relaxation/physiology , Ryanodine Receptor Calcium Release Channel/metabolism , Sarcoplasmic Reticulum/metabolism
4.
Neuromuscul Disord ; 12(1): 13-8, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11731279

ABSTRACT

We present a five-generation family with a novel phenotype of autosomal dominant nemaline myopathy not linked to the three genes known to be causative for nemaline myopathy (alpha-tropomyosin-3, nebulin, and alpha-actin). Although there was muscle weakness in the neck flexors and proximal muscles of the limbs, as found in other families, facial, ankle dorsiflexor and respiratory muscles were normal. The most remarkable clinical feature was a peculiar kind of slowness in movement not reported previously in nemaline myopathy.


Subject(s)
Myopathies, Nemaline/genetics , Myopathies, Nemaline/pathology , Adult , Aged , Biopsy , Family Health , Female , Humans , Male , Microscopy, Electron , Movement Disorders/genetics , Movement Disorders/pathology , Muscle Weakness/genetics , Muscle Weakness/pathology , Myofibrils/pathology , Myofibrils/ultrastructure , Neural Conduction , Pedigree , Phenotype , Tomography, X-Ray Computed
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