Article

Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy

University of Toronto, Toronto, Ontario, Canada
Neuromuscular Disorders (Impact Factor: 3.13). 01/2000; 9(8):564-72. DOI: 10.1016/S0960-8966(99)00061-9
Source: PubMed

ABSTRACT Autosomal recessive nemaline (rod) myopathy is clinically and genetically heterogeneous. A clinically distinct, typical form, with onset in infancy and a non-progressive or slowly progressive course, has been assigned to a region on chromosome 2q22 harbouring the nebulin gene Mutations have now been found in this gene, confirming its causative role. The gene for slow tropomyosin TPM3 on chromosome 1q21, previously found to cause a dominantly inherited form, has recently been found to be homozygously mutated in one severe consanguineous case. Here we wished to determine the degree of genetic homogeneity or heterogeneity of autosomal recessive nemaline myopathy by linkage analysis of 45 families from 10 countries. Forty-one of the families showed linkage results compatible with linkage to markers in the nebulin region, the highest combined lod scores at zero recombination being 14.13 for the marker D2S2236. We found no indication of genetic heterogeneity for the typical form of nemaline myopathy. In four families with more severe forms of nemaline myopathy, however, linkage to both the nebulin and the TPM3 locus was excluded. Our results indicate that at least three genetic loci exist for autosomal recessive nemaline myopathy. Studies of additional families are needed to localise the as yet unknown causative genes, and to fully elucidate genotype-phenotype correlations.

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    • "The congenital muscle disease, nemaline myopathy, is a clinically and genetically heterogeneous condition caused by mutations in genes that encode skeletal muscle thin filament and thin filament-associated proteins (Laing et al., 1995; Nowak et al., 1999; Wallgren-Pettersson et al., 1999; Sanoudou and Beggs, 2001). Patients with nemaline myopathy are clinically defined by skeletal muscle weakness of varying onset and severity and the presence of electron-dense nemaline rods in the skeletal muscles (Wallgren-Pettersson et al., 1999; Sanoudou and Beggs, 2001; Nguyen and Hardeman, 2008). "
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    ABSTRACT: Nemaline myopathy, the most common congenital myopathy, is caused by mutations in genes encoding thin filament and thin filament-associated proteins in skeletal muscles. Severely affected patients fail to survive beyond the first year of life due to severe muscle weakness. There are no specific therapies to combat this muscle weakness. We have generated the first knock-in mouse model for severe nemaline myopathy by replacing a normal allele of the α-skeletal actin gene with a mutated form (H40Y), which causes severe nemaline myopathy in humans. The Acta1(H40Y) mouse has severe muscle weakness manifested as shortened lifespan, significant forearm and isolated muscle weakness and decreased mobility. Muscle pathologies present in the human patients (e.g. nemaline rods, fibre atrophy and increase in slow fibres) were detected in the Acta1(H40Y) mouse, indicating that it is an excellent model for severe nemaline myopathy. Mating of the Acta1(H40Y) mouse with hypertrophic four and a half LIM domains protein 1 and insulin-like growth factor-1 transgenic mice models increased forearm strength and mobility, and decreased nemaline pathologies. Dietary L-tyrosine supplements also alleviated the mobility deficit and decreased the chronic repair and nemaline rod pathologies. These results suggest that L-tyrosine may be an effective treatment for muscle weakness and immobility in nemaline myopathy.
    Brain 11/2011; 134(Pt 12):3516-29. DOI:10.1093/brain/awr274 · 10.23 Impact Factor
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    ABSTRACT: Alcoholic myopathy is characterized by de- creased protein synthesis and contents resulting in atrophy of muscle fibers. We investigated the effect of alcohol on the cytoskeletal muscle proteins, nebulin and titin. Because women are more susceptible than men to the toxic effects of alcohol, male and female rats were included. Four groups were investigated: alcoholic males, pair-fed males, alcoholic females, pair-fed females. Alcohol consumption per unit body weight was 12.9 g/kgd, with no difference between males and females. After 10 wk, male and female rats fed alcohol had lower gastrocnemius and plantaris protein and RNA con- tents (P < 0.001), with no effect on soleus, indicating myop- athy of type II fibers. The gastrocnemius was fractionated to measure myofibrillary protein contents. Low percentage SDS-gel electrophoresis was performed to determine myosin heavy chain (MHC), nebulin and titin contents. Alcohol re- duced gastrocnemius myofibrillary protein and MHC con- tents, and the plantaris RNA/protein ratio (P < 0.01). The titin/MHC and nebulin/MHC ratios were unaffected, suggest- ing a concomitant reduction in titin and nebulin. The de- creases in titin and nebulin contents may affect muscle func- tion. An interaction between gender and alcohol was noted for the plantaris RNA/protein ratio (P < 0.025), suggesting a reduced capacity for muscle protein synthesis in females. J. Nutr. 133: 1154-1157, 2003.
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