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Stephan Lange, Lars Edström, Bjarne Udd, Mathias Gautel, Reply: Hereditary myopathy with early respiratory failure is caused by mutations in the titin FN3 119 domain, Brain, Volume 137, Issue 6, June 2014, Page e279, https://doi.org/10.1093/brain/awu033
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Sir, In the recent letters by Hedberg et al. (2013) and Pfeffer et al. (2013), the important question of genetic variants determining the pathogenesis of human myopathy with early respiratory failure (HMERF) was discussed. We welcome the attention and scientific discussion about the molecular causes and downstream pathogenic alterations in patients affected by this debilitating disease. We recognize the increasing evidence that mutations in titin domain A150 are the major and often dominant cause of HMERF. However, the conclusions the authors draw are debatable for several reasons.
Firstly, the availability of next-generation sequencing, which was not available 9 years ago, allows us now to confirm from our own analysis that all affected members of the originally reported families in (Lange et al., 2005) with the R279W titin kinase (TK) variant (TK nomenclature of residues as in PDB 1TKI to allow comparison) carry a second titin variant in the A150/Fn3 119 domain, P30091L, as also shown in a subset of these patients by Hedberg et al. (2013). Moreover, by clarifying the segregation in the two families and one sporadic patient, we are now able to show that both variants are located in cis on the same allele and not in trans.
