Key result
In vitro characterization of four titin M10 mutations showed three cause severe misfolding or unfolding at 37°C, while I57N behaves like wild-type and may be a silent mutation.
In vitro characterization of titin M10 mutations reveals that three cause misfolding or temperature-sensitive unfolding, while I57N behaves like wild-type, suggesting it may be a silent mutation rather than disease-causing.
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Supports reclassifying I57N as likely benign; leaves open in vivo validation before updating titin variant guidelines.
Rudloff et al. (2015) studied Limb-girdle muscular dystrophy type 2J (LGMD2J) and tibial muscular dystrophy (TMD). Naturally occurring human titin M10 missense mutations vs. Wild-type M10 domain was evaluated on Protein structure, dynamics, and binding to obscurin Ig1 domain. In vitro characterization of four titin M10 mutations showed three cause severe misfolding or unfolding at 37°C, while I57N behaves like wild-type and may be a silent mutation.
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