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Obscurin variants and inherited cardiomyopathies
1Imperial College London, London, UK. s.marston@imperial.ac.uk.
Insights
Mutations in the OBSCN gene, encoding obscurin, are increasingly linked to inherited cardiomyopathies like hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Further research into obscurin
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Basis of Heart Disease
Background:
- Inherited cardiomyopathies, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and left ventricular non-compaction (LVNC), are often linked to sarcomeric protein mutations.
- Giant sarcomeric proteins like titin and nebulin have been studied, but obscurin has been less investigated due to unclear function.
- An early report in 2007 suggested a link between obscurin mutations and HCM.
Purpose of the Study:
- To investigate the role of mutations in the OBSCN gene, encoding obscurin, in inherited cardiomyopathies.
- To determine the prevalence and potential disease-causing nature of OBSCN variants in cardiomyopathy patients.
- To highlight the need for further research into obscurin's function in cardiac pathology.
Main Methods:
- Utilized whole exome sequencing (WES) methodology to identify mutations in the OBSCN gene.
- Analyzed OBSCN variants in cohorts of patients with end-stage heart failure, HCM, and LVNC.
- Reviewed existing literature and genetic survey data regarding OBSCN mutations.
Main Results:
- OBSCN variants were found to be relatively common in inherited cardiomyopathies.
- Specific numbers of unique OBSCN variants were identified in different patient groups: 5 in 30 end-stage failing hearts, 6 in 74 HCM cases, and 3 in 10 LVNC patients.
- The number of known disease-causing OBSCN variants is currently small, partly due to recent recognition and exclusion from earlier large-scale genetic surveys.
Conclusions:
- OBSCN mutations may be causative agents or contributing factors in HCM, DCM, LVNC, and other cardiomyopathies.
- The discovery of OBSCN variants in cardiomyopathy patients suggests a significant role for obscurin in cardiac pathology.
- Anticipate the identification of more OBSCN variants linked to cardiomyopathy as large patient sequence cohorts are analyzed, necessitating further investigation into obscurin's function.
Abstract:
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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