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
N1 - Publisher Copyright:
© 2015 Shigemizu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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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U2 - 10.1371/journal.pone.0130329
DO - 10.1371/journal.pone.0130329
M3 - Article
C2 - 26132555
AN - SCOPUS:84939154610
VL - 10
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 7
M1 - e0130329
ER -