Page 96 - ebook

[A. Biochemistry/Molecular Biology] A-48

Characterization of a novel truncation variant of TBL1

identified in dilated cardiomyopathy

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Hyeong-Jin Kim¹ , Sun-Ho Lee² , Sae-Bom Jeon¹, Hyoeun Kim¹, Jungyoon Choi¹, Jaewon Oh³,
Ho-Geun Yoon¹,², Sahng Wook Park¹,², Seung-Hyun Lee¹,²*

¹Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul 03722, Korea, ²

Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Brain Korea 21 Project,
Yonsei University College of Medicine, Seoul 03722, Korea, ³Division of Cardiology, Severance Cardiovascular

Hospital, Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea

Dilated cardiomyopathy (DCM) is a cardiac disease that causes heart failure and is a leading cause of heart
transplantation. To investigate the genetic causes of DCM, whole-exome sequencing analyses were performed with

a DCM patient and his non-DCM family members. We found a novel homozygous nonsense mutation in exon 15
of the transducin β-like protein (TBL1). Our study found that overexpressed TBL1 truncated variant (TBL1tv) protein

levels were significantly reduced compared to wild-type in H9C2 cell, although there was no difference in the mRNA
levels. In addition, inhibition of proteasome activity by MG132 effectively rescued the reduced protein level of TBL1tv.

These results suggest that massive TBL1tv degradation is proteasome activity-dependent. Previously,
phosphorylation at S470/474 and sumoylation at K560 was identified in the truncated region. We investigated

whether protein stability is regulated by post-translational modification. When the phosphorylation mimic form was
made to the TBL1tv, there was no difference in protein expression level, but it was increased when the sumoylation

residue was added. Furthermore, TBL1 protein expression levels were significantly decreased in human DCM heart
tissues compared to normal tissues. In conclusion, we suggest that decreased TBL1 expression level caused by TBL1

truncation correlated with the development of the DCM.