TTN-related myopathies show considerable clinico-pathological overlap as a group but also with other neuromuscular disorders, in particular the congenital myopathies (CMs), limb girdle muscular dystrophies (LGMDs) and distal myopathies. There is emerging evidence that many of these presentations form part of a continuum of “congenital titinopathy” rather than distinct entities.
Recently, mutations in TTN have emerged as a major cause of both dominantly and recessively inherited myopathies covering a wide and still expanding spectrum (for review ), including tibial muscular dystrophy (TMD), limb girdle muscular dystrophy 2 J (LGMD2J), hereditary myopathy with early respiratory failure (HMERF), Salih myopathy, centronuclear myopathy (CNM), core myopathy with heart disease and childhood-juvenile onset Emery-Dreifuss-like phenotype without cardiomyopathy. In addition to its architectural and mechanical functions in assembling sarcomeres and supporting their contraction and relaxation, the C-terminal, M-band region of titin has emerged as a hub for the coordination of sarcomere proteostasis. The protein contains 132 fibronectin-3 (Fn3) domains, one kinase domain and up to 169 immunoglobulin (Ig) domains, and unstructured regions. Titin is a protein of over 1 µm in length, with a molecular weight in excess of 3 MDa, and is encoded by the TTN gene, which assembles the primary ~ 100 kb transcript from 364 exons in a 300 kb gene. The giant muscle protein titin (also known as connectin) acts as an essential architectural integrator of striated muscle sarcomeres in heart and skeletal muscle by directing the exact subsarcomeric positions of hundreds of other sarcomeric proteins. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. Cardiac involvement depended on the variant position. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants.
The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. Making sense of missense variants in TTN-related congenital myopathies
0 kommentar(er)
