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Reply: Hereditary myopathy with early respiratory failure is caused by mutations in the titin FN3 119 domain

Gerald Pfeffer, Helen Griffin, Angela Pyle, Rita Horvath, Patrick F. Chinnery
DOI: http://dx.doi.org/10.1093/brain/awt306 e271 First published online: 22 November 2013

Sir, The letter from Hedberg et al. (2013) is of great interest because it addresses an important question relating to the genetic aetiology of hereditary myopathy with early respiratory failure (HMERF). The original report by Lange et al. (2005) indicated that HMERF was associated with a heterozygous g.296459C>T/p.R32450W mutation in the kinase domain of titin (TTN) (using Genebank AJ277892 and Uniprot Q8WZ42 as the reference sequences). Since then, no further cases of HMERF caused by kinase domain mutations in TTN have been reported. In contrast, only a year since the report of a mutation in the 119th fibronectin-3 (FN3) domain of TTN causing HMERF (Ohlsson et al., 2012; Pfeffer et al., 2012), numerous reports have confirmed an association between the g.274375T>C/p.C30071R FN3 domain mutation and this disease, and seven other mutations have been reported affecting the same domain of titin (Izumi et al., 2013; Palmio et al., 2013; Pfeffer et al., 2013; Toro et al., 2013). Furthermore, our recent study screening 127 patients with myofibrillar myopathy for mutations in TTN revealed seven families with mutations in the 119th FN3 domain, but none with kinase domain mutations (Pfeffer et al., 2013).

Ostensibly, the patients from Lange et al.’s (2005) original report were from three separate families, although …