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. 2023 Jan 4:13:1087359.
doi: 10.3389/fgene.2022.1087359. eCollection 2022.

Enrichment of titin-truncating variants in exon 327 in dilated cardiomyopathy and its relevance to reduced nonsense-mediated mRNA decay efficiency

Young-Gon Kim  1 , Changhee Ha  1 , Sunghwan Shin  1 , Jong-Ho Park  2 , Ja-Hyun Jang  1 , Jong-Won Kim  1   2
Affiliations

Enrichment of titin-truncating variants in exon 327 in dilated cardiomyopathy and its relevance to reduced nonsense-mediated mRNA decay efficiency

Young-Gon Kim et al. Front Genet. .

Abstract

Titin truncating variants (TTNtvs) are the most common genetic cause of dilated cardiomyopathy (DCM). Among four regions of titin, A-band enrichment of DCM-causing TTNtvs is widely accepted but the underlying mechanism is still unknown. Meanwhile, few reports have identified exon 327 as a highly mutated A-band exon but the degree of exon 327 enrichment has not been quantitatively investigated. To find the real hotspot of DCM-causing TTNtvs, we aimed to reassess the degree of TTNtv enrichment in known titin regions and in exon 327, separately. In addition, we tried to explain exon 327 clustering in terms of nonsense-mediated mRNA decay (NMD) efficiency and a dominant negative mechanism recently proposed. Research papers focusing on TTNtvs found in patients with DCM were collected. A total of 612 patients with TTNtv-realated DCM were obtained from 10 studies. In the four regions of TTN and exon 327, the degree of TTNtvs enrichment was calculated in a way that the effect of distribution of highly expressed exons was normalized. As a result, exon 327 was the only region that showed significant enrichment for DCM-related TTNtv (p < .001). On the other hand, other A-band exons had almost the same number of TTNtv of random distribution. A review of RNAseq data revealed that the median allelic imbalance deviation of exon 327 TTNtvs was .04, indicating almost zero NMD. From these findings, we propose that the widely accepted A-band enrichment of DCM-related TTNtv is mostly attributable to exon 327 enrichment. In addition, based on the recently demonstrated dominant negative mechanism, the extremely low NMD efficiency seems to contribute to exon 327 enrichment.

Keywords: TTN; dilated cardiomyopathy; exon 327; nonsense-mediated mRNA decay; truncating variant.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
(A) Four regions of titin meta-transcript (NM_001267550.2) with PSI (Percent spliced-in) distribution. (B) After low-PSI exons were removed, I-band was divided into two sub-regions (Proximal I-band: exon 29–50, Distal I-band: exon 220–252), and A-band was divided into three sub-regions (Pre-exon 327: exon 253–326, exon 327, post-exon 327: exon 328–358). (C) Degree of Titin-truncating variant (TTNtv) enrichment calculated based on the ratio of observed and expected (based on the length of the region) number of TTNtv. (A) DCM group (B) gnomAD group (C) DCM group/gnomAD group.
FIGURE 2
FIGURE 2
Forest plot showing the degree of titin-truncating variant (TTNtv) enrichment in exon 327 from individual studies.
FIGURE 3
FIGURE 3
(A) Relationship between Premature termination codon (PTC)-to-intron distance and allelic imbalance deviation (AI deviation). (B) Difference in nonsense-mediated mRNA decay efficiency measured by AI deviation level between exon 327 and non-exon 327 titin-truncating variants (TTNtvs). Median PTC-to-intron distance was 10,693 and 223 in exon 327 group and non-exon 327 TTNtvs, respectively (p < .001). (C) Relationship between PTC-to-intron distance and age of heart transplantation in carriers of exon 327 TTNtv. (D) Relationship between AI deviation and age of heart transplantation in carriers of exon 327 TTNtvs. p-values are from Pearson’s correlation test and the Mann–Whitney test. PTC, premature termination codon; AI, allelic imbalance; TTNtv, titin-truncating variant.
FIGURE 4
FIGURE 4
Long PTC-to-intron distance of Exon 327 TTNtvs leading to extremely low NMD efficiency.
See this image and copyright information in PMC

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