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Hereditary myopathy with early respiratory failure is an autosomal dominant myopathy caused by mutations in the 119th fibronectin-3 domain of titin. To date all reported patients with the most common mutation in this domain (p.C30071R) appear to share ancestral disease alleles. We undertook this study of two families with the p.C30071R mutation to determine whether they share the same haplotype as previously reported British families or whether the mutation arose as a de novo event. We sequenced the 119th fibronectin-3 domain in these two probands and flanking polymorphisms associated with the British haplotype in hereditary myopathy with early respiratory failure. A family of Indian descent had a haplotype that was not compatible with the British shared haplotype. Cloning of the 119th fibronectin-3 domain in this patient demonstrated polymorphisms rs191484894 and novel noncoding variant c.90225C>T on the same allele as the mutation, which is distinct from previously reported British families. This proves that the p.C30071R mutation itself (rather than the haplotype containing this mutation) causes hereditary myopathy with early respiratory failure and suggests its independent origin in different ethnic groups., (Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Titin gene (TTN) mutations have been described in eight families with hereditary myopathy with early respiratory failure (HMERF). Some of the original patients had features resembling myofibrillar myopathy (MFM), arguing that TTN mutations could be a much more common cause of inherited muscle disease, especially in presence of early respiratory involvement., Methods: We studied 127 undiagnosed patients with clinical presentation compatible with MFM. Sanger sequencing for the two previously described TTN mutations in HMERF (p.C30071R in the 119th fibronectin-3 (FN3) domain, and p.R32450W in the kinase domain) was performed in all patients. Patients with mutations had detailed review of their clinical records, muscle MRI findings and muscle pathology., Results: We identified five new families with the p.C30071R mutation who were clinically similar to previously reported cases, and muscle pathology demonstrated diagnostic features of MFM. Two further families had novel variants in the 119th FN3 domain (p.P30091L and p.N30145K). No patients were identified with mutations at position p.32450., Conclusions: Mutations in TTN are a cause of MFM, and titinopathy is more common than previously thought. The finding of the p.C30071R mutation in 3.9% of our study population is likely due to a British founder effect. The occurrence of novel FN3 domain variants, although still of uncertain pathogenicity, suggests that other mutations in this domain may cause MFM, and that the disease is likely to be globally distributed. We suggest that HMERF due to mutations in the TTN gene be nosologically classified as MFM-titinopathy.

Titin gene (TTN) mutations have been described in 8 families with hereditary myopathy with early respiratory failure (HMERF) a rare condition with features resembling myofibrillar myopathy (MFM). In order to verify if TTN mutations could be a cause of MFM, especially in presence of early respiratory involvement, we carried out a clinical and genetic analysis of 127 undiagnosed patients with a clinical presentation compatible with MFM. Sanger sequencing for the TTN mutations previously described in patients with HMERF (p.C30071R and p.R32450W) was performed in all patients. We identified 5 families with the p.C30071R mutation (3.9% of study population) likely due to a British founder effect. Affected subjects showed phenotypic features similar to previously reported cases, and muscle pathology demonstrated diagnostic features of MFM. Two further families had novel variants in the 119th FN3 domain (p.P30091L and p.N30145K). Although still with uncertain pathogenicity, these new variants suggest that other TTN mutations in this domain may cause MFM. Our results indicate that mutations in TTN gene cause MFM and titinopathy is more common than previously thought. We suggest that HMERF due to mutations in the TTN gene be nosologically classified as MFM-titinopathy. [Copyright &y& Elsevier]

Hereditary myopathy with early respiratory failure (HMERF) caused by A-band TTN mutations shows a clinical and histopathological overlap with myofibrillar myopathies (MFM) characterized by disintegration of myofibrils and protein aggregation in muscle fibers. We applied a proteomic approach to decipher the aggregate composition in HMERF and compared the proteomic profile with findings in MFM subtypes. Nine skeletal muscle samples from HMERF patients with three different mutations in A-band titin and histopathological findings consistent with MFM were analyzed. Protein aggregates and intraindividual control samples (from aggregate-free muscle fibers) were collected by laser microdissection and analysed by a label-free mass spectrometric approach for identification and relative quantification of proteins. Fifty-eight proteins showed a statistically significant accumulation in aggregates with a ratio >1.8 compared to control samples. The over-represented proteins desmin, filamin C, Xirp2, N-RAP, alphaB-crystallin, nestin, myotilin, Xin and Hsp27 were highly abundant in aggregates. The same was found in different MFM subtypes. The detection of further Z-disc proteins, chaperones, proteins involved in protein degradation and sarcolemmal proteins was also typical of MFM. In addition, we identified an over-representation of proteins that are involved in signaling pathways (e.g. inhibitors of the Rho/ROCK signaling pathway and ankyrin repeat domain-containing proteins). Titin was slightly but significant under-represented in aggregates (ratio 0.83). In conclusion, the proteomic profile of aggregates in HMERF associated with mutations in A-band titin is typical of MFM and confirms that this type of titinopathy is a new MFM subtype. The finding that titin is under-represented in aggregates indicates that aggregate formation is mediated by secondary effects. The detected over-representation of proteins involved in signaling pathways may play a role in pathogenesis. [Copyright &y& Elsevier]

Hereditary myopathy with early respiratory failure (HMERF) is caused by A-band titin mutations and characterized by myofibrillar alterations and protein aggregation in skeletal muscle fibers. Our previous studies revealed that the composition of myotilin-positive aggregates is comparable to that seen in myofibrillar myopathies (MFM). However, there are two different types of protein aggregates in HMERF: subsarcolemmal cytoplasmic bodies (CB) with a dense filamentous core and non-CB aggregates. The aim of this study was to compare the proteomic profile of these protein deposits. We used Gomori trichrome stained skeletal muscle sections from two HMERF patients to separately collect CB, non-CB aggregates and intraindividual control samples by laser microdissection and performed a highly sensitive label-free mass spectrometry approach for protein detection and relative quantification based on spectral counting. The proteomic profiles of CB and non-CB aggregates showed a high degree of similarity: XIRP2, desmin, filamin C, N-RAP, nestin, COL6A3, myotilin, sarcosin, αB-crystallin, dystrophin, XIN and aciculin ranked among the most abundant over-represented proteins (ratio >1.5 compared to control samples) in both aggregate types. Peptides assigned to these twelve proteins accounted for 69% (CB) and 75% (non-CB aggregates) of all peptides assigned to over-represented proteins and the individual proportions of these proteins were almost the same. We also detected similarities in less abundant over-represented proteins. Titin was under-represented in CB (ratio 0.81) and in non-CB aggregates (ratio 0.80). In conclusion, our analysis revealed that the proteomic profiles of CB and non-CB aggregates are highly similar in HMERF, especially regarding abundant over-represented proteins, and typical of MFM aggregates. [ABSTRACT FROM AUTHOR]