Exome analyses of long QT syndrome reveal candidate pathogenic mutations in calmodulin-interacting genes

Daichi Shigemizu, Takeshi Aiba, Hidewaki Nakagawa, Kouichi Ozaki, Fuyuki Miya, Wataru Satake, Tatsushi Toda, Yoshihiro Miyamoto, Akihiro Fujimoto, Yutaka Suzuki, Michiaki Kubo, Tatsuhiko Tsunoda, Wataru Shimizu, Toshihiro Tanaka

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10 Citations (Scopus)

Abstract

Long QT syndrome (LQTS) is an arrhythmogenic disorder that can lead to sudden death. To date, mutations in 15 LQTS-susceptibility genes have been implicated. However, the genetic cause for approximately 20% of LQTS patients remains elusive. Here, we performed whole-exome sequencing analyses on 59 LQTS and 61 unaffected individuals in 35 families and 138 unrelated LQTS cases, after genetic screening of known LQTS genes. Our systematic analysis of familial cases and subsequent verification by Sanger sequencing identified 92 candidate mutations in 88 genes for 23 of the 35 families (65.7%): these included eleven de novo, five recessive (two homozygous and three compound heterozygous) and seventy-three dominant mutations. Although no novel commonly mutated gene was identified other than known LQTS genes, protein-protein interaction (PPI) network analyses revealed ten new pathogenic candidates that directly or indirectly interact with proteins encoded by known LQTS genes. Furthermore, candidate gene based association studies using an independent set of 138 unrelated LQTS cases and 587 controls identified an additional novel candidate. Together, mutations in these new candidates and known genes explained 37.1% of the LQTS families (13 in 35). Moreover, half of the newly identified candidates directly interact with calmodulin (5 in 11; comparison with all genes; p=0.042). Subsequent variant analysis in the independent set of 138 cases identified 16 variants in the 11 genes, of which 14 were in calmodulin-interacting genes (87.5%). These results suggest an important role of calmodulin and its interacting proteins in the pathogenesis of LQTS.

Original languageEnglish
Article numbere0130329
JournalPLoS One
Volume10
Issue number7
DOIs
Publication statusPublished - 01-07-2015
Externally publishedYes

Fingerprint

Exome
Long QT Syndrome
calmodulin
Calmodulin
Genes
mutation
Mutation
genes
Proteins
Protein Interaction Maps
Genetic Testing
Genetic Association Studies
protein-protein interactions
Sudden Death
Screening
pathogenesis
proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Shigemizu, D., Aiba, T., Nakagawa, H., Ozaki, K., Miya, F., Satake, W., ... Tanaka, T. (2015). Exome analyses of long QT syndrome reveal candidate pathogenic mutations in calmodulin-interacting genes. PLoS One, 10(7), [e0130329]. https://doi.org/10.1371/journal.pone.0130329
Shigemizu, Daichi ; Aiba, Takeshi ; Nakagawa, Hidewaki ; Ozaki, Kouichi ; Miya, Fuyuki ; Satake, Wataru ; Toda, Tatsushi ; Miyamoto, Yoshihiro ; Fujimoto, Akihiro ; Suzuki, Yutaka ; Kubo, Michiaki ; Tsunoda, Tatsuhiko ; Shimizu, Wataru ; Tanaka, Toshihiro. / Exome analyses of long QT syndrome reveal candidate pathogenic mutations in calmodulin-interacting genes. In: PLoS One. 2015 ; Vol. 10, No. 7.
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abstract = "Long QT syndrome (LQTS) is an arrhythmogenic disorder that can lead to sudden death. To date, mutations in 15 LQTS-susceptibility genes have been implicated. However, the genetic cause for approximately 20{\%} of LQTS patients remains elusive. Here, we performed whole-exome sequencing analyses on 59 LQTS and 61 unaffected individuals in 35 families and 138 unrelated LQTS cases, after genetic screening of known LQTS genes. Our systematic analysis of familial cases and subsequent verification by Sanger sequencing identified 92 candidate mutations in 88 genes for 23 of the 35 families (65.7{\%}): these included eleven de novo, five recessive (two homozygous and three compound heterozygous) and seventy-three dominant mutations. Although no novel commonly mutated gene was identified other than known LQTS genes, protein-protein interaction (PPI) network analyses revealed ten new pathogenic candidates that directly or indirectly interact with proteins encoded by known LQTS genes. Furthermore, candidate gene based association studies using an independent set of 138 unrelated LQTS cases and 587 controls identified an additional novel candidate. Together, mutations in these new candidates and known genes explained 37.1{\%} of the LQTS families (13 in 35). Moreover, half of the newly identified candidates directly interact with calmodulin (5 in 11; comparison with all genes; p=0.042). Subsequent variant analysis in the independent set of 138 cases identified 16 variants in the 11 genes, of which 14 were in calmodulin-interacting genes (87.5{\%}). These results suggest an important role of calmodulin and its interacting proteins in the pathogenesis of LQTS.",
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Shigemizu, D, Aiba, T, Nakagawa, H, Ozaki, K, Miya, F, Satake, W, Toda, T, Miyamoto, Y, Fujimoto, A, Suzuki, Y, Kubo, M, Tsunoda, T, Shimizu, W & Tanaka, T 2015, 'Exome analyses of long QT syndrome reveal candidate pathogenic mutations in calmodulin-interacting genes', PLoS One, vol. 10, no. 7, e0130329. https://doi.org/10.1371/journal.pone.0130329

Exome analyses of long QT syndrome reveal candidate pathogenic mutations in calmodulin-interacting genes. / Shigemizu, Daichi; Aiba, Takeshi; Nakagawa, Hidewaki; Ozaki, Kouichi; Miya, Fuyuki; Satake, Wataru; Toda, Tatsushi; Miyamoto, Yoshihiro; Fujimoto, Akihiro; Suzuki, Yutaka; Kubo, Michiaki; Tsunoda, Tatsuhiko; Shimizu, Wataru; Tanaka, Toshihiro.

In: PLoS One, Vol. 10, No. 7, e0130329, 01.07.2015.

Research output: Contribution to journal › Article

TY - JOUR

T1 - Exome analyses of long QT syndrome reveal candidate pathogenic mutations in calmodulin-interacting genes

AU - Shigemizu, Daichi

AU - Aiba, Takeshi

AU - Nakagawa, Hidewaki

AU - Ozaki, Kouichi

AU - Miya, Fuyuki

AU - Satake, Wataru

AU - Toda, Tatsushi

AU - Miyamoto, Yoshihiro

AU - Fujimoto, Akihiro

AU - Suzuki, Yutaka

AU - Kubo, Michiaki

AU - Tsunoda, Tatsuhiko

AU - Shimizu, Wataru

AU - Tanaka, Toshihiro

PY - 2015/7/1

Y1 - 2015/7/1

N2 - Long QT syndrome (LQTS) is an arrhythmogenic disorder that can lead to sudden death. To date, mutations in 15 LQTS-susceptibility genes have been implicated. However, the genetic cause for approximately 20% of LQTS patients remains elusive. Here, we performed whole-exome sequencing analyses on 59 LQTS and 61 unaffected individuals in 35 families and 138 unrelated LQTS cases, after genetic screening of known LQTS genes. Our systematic analysis of familial cases and subsequent verification by Sanger sequencing identified 92 candidate mutations in 88 genes for 23 of the 35 families (65.7%): these included eleven de novo, five recessive (two homozygous and three compound heterozygous) and seventy-three dominant mutations. Although no novel commonly mutated gene was identified other than known LQTS genes, protein-protein interaction (PPI) network analyses revealed ten new pathogenic candidates that directly or indirectly interact with proteins encoded by known LQTS genes. Furthermore, candidate gene based association studies using an independent set of 138 unrelated LQTS cases and 587 controls identified an additional novel candidate. Together, mutations in these new candidates and known genes explained 37.1% of the LQTS families (13 in 35). Moreover, half of the newly identified candidates directly interact with calmodulin (5 in 11; comparison with all genes; p=0.042). Subsequent variant analysis in the independent set of 138 cases identified 16 variants in the 11 genes, of which 14 were in calmodulin-interacting genes (87.5%). These results suggest an important role of calmodulin and its interacting proteins in the pathogenesis of LQTS.

AB - Long QT syndrome (LQTS) is an arrhythmogenic disorder that can lead to sudden death. To date, mutations in 15 LQTS-susceptibility genes have been implicated. However, the genetic cause for approximately 20% of LQTS patients remains elusive. Here, we performed whole-exome sequencing analyses on 59 LQTS and 61 unaffected individuals in 35 families and 138 unrelated LQTS cases, after genetic screening of known LQTS genes. Our systematic analysis of familial cases and subsequent verification by Sanger sequencing identified 92 candidate mutations in 88 genes for 23 of the 35 families (65.7%): these included eleven de novo, five recessive (two homozygous and three compound heterozygous) and seventy-three dominant mutations. Although no novel commonly mutated gene was identified other than known LQTS genes, protein-protein interaction (PPI) network analyses revealed ten new pathogenic candidates that directly or indirectly interact with proteins encoded by known LQTS genes. Furthermore, candidate gene based association studies using an independent set of 138 unrelated LQTS cases and 587 controls identified an additional novel candidate. Together, mutations in these new candidates and known genes explained 37.1% of the LQTS families (13 in 35). Moreover, half of the newly identified candidates directly interact with calmodulin (5 in 11; comparison with all genes; p=0.042). Subsequent variant analysis in the independent set of 138 cases identified 16 variants in the 11 genes, of which 14 were in calmodulin-interacting genes (87.5%). These results suggest an important role of calmodulin and its interacting proteins in the pathogenesis of LQTS.

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Shigemizu D, Aiba T, Nakagawa H, Ozaki K, Miya F, Satake W et al. Exome analyses of long QT syndrome reveal candidate pathogenic mutations in calmodulin-interacting genes. PLoS One. 2015 Jul 1;10(7). e0130329. https://doi.org/10.1371/journal.pone.0130329

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