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
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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)