2010/12/03 by M. A. Sandberg, Michael A. Sandberg, B. Rosner +4 · 9 citations
Medicine · Biochemistry, Genetics and Molecular Biology · #Peptidase Inhibition and Analysis #Cardiomyopathy and Myosin Studies #Muscle Physiology and Disorders
paper · doi:10.1136/bjo.2010.198176
<h3>Background</h3> Congenital nemaline myopathies are rare pathologies characterised by muscle weakness and rod-shaped inclusions in the muscle fibres. <h3>Methods</h3> Using next-generation sequencing, we identified three patients with pathogenic variants in the <i>Troponin T type 1</i> (<i>TNNT1</i>) gene, coding for the troponin T (TNT) skeletal muscle isoform. <h3>Results</h3> The clinical phenotype was similar in all patients, associating hypotonia, orthopaedic deformities and progressive chronic respiratory failure, leading to early death. The anatomopathological phenotype was characterised by a disproportion in the muscle fibre size, endomysial fibrosis and nemaline rods. Molecular analyses of <i>TNNT1</i> revealed a homozygous deletion of exons 8 and 9 in patient 1; a heterozygous nonsense mutation in exon 9 and retention of part of intron 4 in muscle transcripts in patient 2; and a homozygous, very early nonsense mutation in patient 3. Western blot analyses confirmed the absence of the TNT protein resulting from these mutations. <h3>Discussion</h3> The clinical and anatomopathological presentations of our patients reinforce the homogeneous character of the phenotype associated with recessive <i>TNNT1</i> mutations. Previous studies revealed an impact of recessive variants on the tropomyosin-binding affinity of TNT. We report in our patients a complete loss of TNT protein due to open reading frame disruption or to post-translational degradation of TNT.