Obscurin variants and inherited cardiomyopathies

Biophysical Reviews, May 2017

The inherited cardiomyopathies, hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and left ventricular non-compaction (LVNC), have been frequently associated with mutations in sarcomeric proteins. In recent years, advances in DNA sequencing technology has allowed the study of the giant proteins of the sarcomere, such as titin and nebulin. Obscurin has been somewhat neglected in these studies, largely because its functional role is far from clear, although there was an isolated report in 2007 of obscurin mutations associated with HCM. Recently, whole exome sequencing methodology (WES) has been used to address mutations in OBSCN, the gene for obscurin, and OBSCN variants were found to be relatively common in inherited cardiomyopathies. In different studies, 5 OBSCN unique variants have been found in a group of 30 end-stage failing hearts, 6 OBSCN unique variants in 74 HCM cases and 3 OBSCN unique variants in 10 LVNC patients. As yet, the number of known potentially disease-causing OBSCN variants is quite small. The reason for this is that mutations in the OBSCN gene have not been recognised as potentially disease-causing until recently, and were not included in large-scale genetic surveys. OBSCN mutations may be causative of HCM, DCM and LVNC and other cardiomyopathies, or they may work in concert with other variants in the same or other genes to initiate the pathology. Currently, the function of obscurin is not well understood, but we anticipate that many more OBSCN variants linked to cardiomyopathy will be found when the large cohorts of patient sequences available are tested. It is to be hoped that the establishment of the importance of obscurin in pathology will stimulate a thorough investigation of obscurin function.

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Obscurin variants and inherited cardiomyopathies

Biophys Rev Obscurin variants and inherited cardiomyopathies 0 Imperial College London , London , UK 1 Steven Marston The inherited cardiomyopathies, hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and left ventricular non-compaction (LVNC), have been frequently associated with mutations in sarcomeric proteins. In recent years, advances in DNA sequencing technology has allowed the study of the giant proteins of the sarcomere, such as titin and nebulin. Obscurin has been somewhat neglected in these studies, largely because its functional role is far from clear, although there was an isolated report in 2007 of obscurin mutations associated with HCM. Recently, whole exome sequencing methodology (WES) has been used to address mutations in OBSCN, the gene for obscurin, and OBSCN variants were found to be relatively common in inherited cardiomyopathies. In different studies, 5 OBSCN unique variants have been found in a group of 30 end-stage failing hearts, 6 OBSCN unique variants in 74 HCM cases and 3 OBSCN unique variants in 10 LVNC patients. As yet, the number of known potentially disease-causing OBSCN variants is quite small. The reason for this is that mutations in the OBSCN gene have not been recognised as potentially disease-causing until recently, and were not included in large-scale genetic surveys. OBSCN mutations may be causative of HCM, DCM and LVNC and other cardiomyopathies, or they may work in concert with other variants in the same or other genes to initiate the pathology. Currently, the function of obscurin is not well understood, but we anticipate that many more OBSCN variants linked to cardiomyopathy will be found when the large cohorts of patient sequences available are tested. It is to be hoped that the establishment of the importance of obscurin in pathology will stimulate a thorough investigation of obscurin function. Cardiac muscle; Obscurin; Mutation; Dilated carriomyopathy; Hypertrophic cardiomyopathy - The inherited cardiomyopathies, particularly hypertrophic cardiomyopathy (HCM) dilated cardiomyopathy (DCM) and left ventricular non-compaction (LVNC), have been frequently associated with mutations in the sarcomeric proteins. In recent years, advances in DNA sequencing technology have allowed the study of the giant proteins of the sarcomere, notably truncating mutations in the titin gene (TTNtv), which have been found to be responsible for up to 25% of familial DCM cases (Roberts et al. 2015) , and mutations in nebulin (NEB), the most common mutations causing skeletal muscle myopathies such as nemaline myopathy (Lehtokari et al. 2014) . Obscurin has been somewhat neglected in these studies, largely because its functional role is far from clear. There was an isolated report in 2007 of obscurin mutations associated with HCM but this was not followed up for several years. Recently, whole exome sequencing methodology (WES) has been used to address mutations in OBSCN, the gene for obscurin, and OBSCN variants were found to be relatively common in inherited cardiomyopathies. Marston et al.’s (2015) study found 5 OBSCN unique variants in 4 individual hearts from a group of 30 end-stage failing hearts, Xu et al. (2015) found 6 OBSCN unique variants in 74 HCM cases and Rowland et al. (2016) found 4 OBSCN unique variants in 335 DCM and LVNC patients, of which OBSCN variants were associated with 3 out of 11 LVNC cases (Table 1). Pathology Domain Ob58 Ob59 Ob 9 Ob 21 Ob 27 Ob 47 PH Between Ob66 and Ob67 Between kinase I and Ob69 Between kinase I and Ob69 Ob 10 Ob 11 Ob13 Ob 17 Ob 69 The locations of the mutations are shown in the obscurin B sequence in Fig. 1. Note that the published amino acid numbers in Rowland et al. 2016 were based on NP_001258152 and have been converted to NP_001092093 numbering for comparison On this basis, potentially disease-causing OBSCN variants seem to be fairly common in all three diseases. As yet, the number of known potentially disease-causing OBSCN variants is quite small. The reason for this is that mutations in the OBSCN gene have not been recognised as potentially diseasecausing until recently, and are not included in current largescale genetic surveys, For instance, Alfares et al. (2015) studied 2912 HCM cases, Ware et al. (2016) studied 172 peripartum cardiomyopathy cases and Haas et al. (2014) studied 639 DCM cases. It is noteworthy that the largest study to date, in which 46 genes in 7855 cardiomyopathy cases were compared with 60,706 reference samples, did not analyse variants in the OBSCN gene (Walsh et al. 2017) . We anticipate that, when these large cohorts are re-examined for OBSCN diseaserelated variants, a considerable number will be found. All the recent studies on OBSCN variants have involved whole exon sequencing with the unique variants being identified by comparison with large reference databases, such as Exacs and EVS, and their pathogenicity predicted using algorithms such as SIFT. This approach, based on (...truncated)


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Steven Marston. Obscurin variants and inherited cardiomyopathies, Biophysical Reviews, 2017, pp. 239-243, Volume 9, Issue 3, DOI: 10.1007/s12551-017-0264-8