Cargando…

High prevalence of Arginine to Glutamine Substitution at 98, 141 and 162 positions in Troponin I (TNNI3) associated with hypertrophic cardiomyopathy among Indians

BACKGROUND: Troponin I (TNNI3) is the inhibitory subunit of the thin filament regulatory complex Troponin, which confers calcium-sensitivity to striated muscle actomyosin ATPase activity. Mutations (2-7%) in this gene had been reported in hypertrophic cardiomyopathy patients (HCM). However, the freq...

Descripción completa

Detalles Bibliográficos
Autores principales: Rani, Deepa Selvi, Nallari, Pratibha, Priyamvada, Singh, Narasimhan, Calambur, Singh, Lalji, Thangaraj, Kumarasamy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495047/
https://www.ncbi.nlm.nih.gov/pubmed/22876777
http://dx.doi.org/10.1186/1471-2350-13-69
_version_ 1782249460344029184
author Rani, Deepa Selvi
Nallari, Pratibha
Priyamvada, Singh
Narasimhan, Calambur
Singh, Lalji
Thangaraj, Kumarasamy
author_facet Rani, Deepa Selvi
Nallari, Pratibha
Priyamvada, Singh
Narasimhan, Calambur
Singh, Lalji
Thangaraj, Kumarasamy
author_sort Rani, Deepa Selvi
collection PubMed
description BACKGROUND: Troponin I (TNNI3) is the inhibitory subunit of the thin filament regulatory complex Troponin, which confers calcium-sensitivity to striated muscle actomyosin ATPase activity. Mutations (2-7%) in this gene had been reported in hypertrophic cardiomyopathy patients (HCM). However, the frequencies of mutations and associated clinical presentation have not been established in cardiomyopathy patients of Indian origin, hence we have undertaken this study. METHODS: We have sequenced all the exons, including the exon-intron boundaries of TNNI3 gene in 101 hypertrophic cardiomyopathy patients (HCM), along with 160 healthy controls, inhabited in the same geographical region of southern India. RESULTS: Our study revealed a total of 16 mutations. Interestingly, we have observed Arginine to Glutamine (R to Q) mutation at 3 positions 98, 141 and 162, exclusively in HCM patients with family history of sudden cardiac death. The novel R98Q was observed in a severe hypertrophic obstructive cardiomyopathy patient (HOCM). The R141Q mutation was observed in two familial cases of severe asymmetric septal hypertrophy (ASH++). The R162Q mutation was observed in a ASH++ patient with mean septal thickness of 29 mm, and have also consists of allelic heterogeneity by means of having one more synonymous (E179E) mutation at g.4797: G → A: in the same exon 7, which replaces a very frequent codon (GAG: 85%) with a rare codon (GAA: 14%). Screening for R162Q mutation in all the available family members revealed its presence in 9 individuals, including 7 with allelic heterogeneity (R162Q and E179E) of which 4 were severely affected. We also found 2 novel SNPs, (g.2653; G → A and g.4003 C → T) exclusively in HCM, and in silico analysis of these SNPs have predicted to cause defect in recognition/binding sites for proteins responsible for proper splicing. CONCLUSION: Our study has provided valuable information regarding the prevalence of TNNI3 mutations in Indian HCM patients and its risk assessment, these will help in genetic counseling and to adopt appropriate treatment strategies.
format Online
Article
Text
id pubmed-3495047
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-34950472012-11-11 High prevalence of Arginine to Glutamine Substitution at 98, 141 and 162 positions in Troponin I (TNNI3) associated with hypertrophic cardiomyopathy among Indians Rani, Deepa Selvi Nallari, Pratibha Priyamvada, Singh Narasimhan, Calambur Singh, Lalji Thangaraj, Kumarasamy BMC Med Genet Research Article BACKGROUND: Troponin I (TNNI3) is the inhibitory subunit of the thin filament regulatory complex Troponin, which confers calcium-sensitivity to striated muscle actomyosin ATPase activity. Mutations (2-7%) in this gene had been reported in hypertrophic cardiomyopathy patients (HCM). However, the frequencies of mutations and associated clinical presentation have not been established in cardiomyopathy patients of Indian origin, hence we have undertaken this study. METHODS: We have sequenced all the exons, including the exon-intron boundaries of TNNI3 gene in 101 hypertrophic cardiomyopathy patients (HCM), along with 160 healthy controls, inhabited in the same geographical region of southern India. RESULTS: Our study revealed a total of 16 mutations. Interestingly, we have observed Arginine to Glutamine (R to Q) mutation at 3 positions 98, 141 and 162, exclusively in HCM patients with family history of sudden cardiac death. The novel R98Q was observed in a severe hypertrophic obstructive cardiomyopathy patient (HOCM). The R141Q mutation was observed in two familial cases of severe asymmetric septal hypertrophy (ASH++). The R162Q mutation was observed in a ASH++ patient with mean septal thickness of 29 mm, and have also consists of allelic heterogeneity by means of having one more synonymous (E179E) mutation at g.4797: G → A: in the same exon 7, which replaces a very frequent codon (GAG: 85%) with a rare codon (GAA: 14%). Screening for R162Q mutation in all the available family members revealed its presence in 9 individuals, including 7 with allelic heterogeneity (R162Q and E179E) of which 4 were severely affected. We also found 2 novel SNPs, (g.2653; G → A and g.4003 C → T) exclusively in HCM, and in silico analysis of these SNPs have predicted to cause defect in recognition/binding sites for proteins responsible for proper splicing. CONCLUSION: Our study has provided valuable information regarding the prevalence of TNNI3 mutations in Indian HCM patients and its risk assessment, these will help in genetic counseling and to adopt appropriate treatment strategies. BioMed Central 2012-08-10 /pmc/articles/PMC3495047/ /pubmed/22876777 http://dx.doi.org/10.1186/1471-2350-13-69 Text en Copyright ©2012 Rani et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Rani, Deepa Selvi
Nallari, Pratibha
Priyamvada, Singh
Narasimhan, Calambur
Singh, Lalji
Thangaraj, Kumarasamy
High prevalence of Arginine to Glutamine Substitution at 98, 141 and 162 positions in Troponin I (TNNI3) associated with hypertrophic cardiomyopathy among Indians
title High prevalence of Arginine to Glutamine Substitution at 98, 141 and 162 positions in Troponin I (TNNI3) associated with hypertrophic cardiomyopathy among Indians
title_full High prevalence of Arginine to Glutamine Substitution at 98, 141 and 162 positions in Troponin I (TNNI3) associated with hypertrophic cardiomyopathy among Indians
title_fullStr High prevalence of Arginine to Glutamine Substitution at 98, 141 and 162 positions in Troponin I (TNNI3) associated with hypertrophic cardiomyopathy among Indians
title_full_unstemmed High prevalence of Arginine to Glutamine Substitution at 98, 141 and 162 positions in Troponin I (TNNI3) associated with hypertrophic cardiomyopathy among Indians
title_short High prevalence of Arginine to Glutamine Substitution at 98, 141 and 162 positions in Troponin I (TNNI3) associated with hypertrophic cardiomyopathy among Indians
title_sort high prevalence of arginine to glutamine substitution at 98, 141 and 162 positions in troponin i (tnni3) associated with hypertrophic cardiomyopathy among indians
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495047/
https://www.ncbi.nlm.nih.gov/pubmed/22876777
http://dx.doi.org/10.1186/1471-2350-13-69
work_keys_str_mv AT ranideepaselvi highprevalenceofargininetoglutaminesubstitutionat98141and162positionsintroponinitnni3associatedwithhypertrophiccardiomyopathyamongindians
AT nallaripratibha highprevalenceofargininetoglutaminesubstitutionat98141and162positionsintroponinitnni3associatedwithhypertrophiccardiomyopathyamongindians
AT priyamvadasingh highprevalenceofargininetoglutaminesubstitutionat98141and162positionsintroponinitnni3associatedwithhypertrophiccardiomyopathyamongindians
AT narasimhancalambur highprevalenceofargininetoglutaminesubstitutionat98141and162positionsintroponinitnni3associatedwithhypertrophiccardiomyopathyamongindians
AT singhlalji highprevalenceofargininetoglutaminesubstitutionat98141and162positionsintroponinitnni3associatedwithhypertrophiccardiomyopathyamongindians
AT thangarajkumarasamy highprevalenceofargininetoglutaminesubstitutionat98141and162positionsintroponinitnni3associatedwithhypertrophiccardiomyopathyamongindians