Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology

S. C. Menon, V. V. Michels, Patricia Pellikka, J. D. Ballew, M. L. Karst, K. J. Herron, S. M. Nelson, R. J. Rodeheffer, Timothy Mark Olson

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

We identified a unique family with autosomal dominant heart disease variably expressed as restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM), and sought to identify the molecular defect that triggered divergent remodeling pathways. Polymorphic DNA markers for nine sarcomeric genes for DCM and/ or HCM were tested for segregation with disease. Linkage to eight genes was excluded, but a cardiac troponin T (TNNT2) marker cosegregated with the disease phenotype. Sequencing of TNNT2 identified a heterozygous missense mutation resulting in an I79N substitution, inherited by all nine affected family members but by none of the six unaffected relatives. Mutation carriers were diagnosed with RCM (n = 2), non-obstructive HCM (n = 3), DCM (n = 2), mixed cardiomyopathy (n = 1), and mild concentric left ventricular hypertrophy (n = 1). Endomyocardial biopsy in the proband revealed non-specific fibrosis, myocyte hypertrophy, and no myofibrillar disarray. Restrictive Doppler filling patterns, atrial enlargement, and pulmonary hypertension were observed among family members regardless of cardiomyopathy subtype. Mutation of a sarcomeric protein gene can cause RCM, HCM, and DCM within the same family, underscoring the necessity of comprehensive morphological and physiological cardiac assessment in familial cardiomyopathy screening.

Original languageEnglish (US)
Pages (from-to)445-454
Number of pages10
JournalClinical Genetics
Volume74
Issue number5
DOIs
StatePublished - 2008

Fingerprint

Troponin T
Hypertrophic Cardiomyopathy
Restrictive Cardiomyopathy
Dilated Cardiomyopathy
Cardiomyopathies
Mutation
Left Ventricular Hypertrophy
Missense Mutation
Genetic Markers
Pulmonary Hypertension
Muscle Cells
Hypertrophy
Genes
Heart Diseases
Fibrosis
Phenotype
Biopsy
Proteins

Keywords

  • Dilated cardiomyopathy
  • Hypertrophic cardiomyopathy
  • Mutation
  • Restrictive cardiomyopathy
  • Sarcomere
  • TNNT2

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology. / Menon, S. C.; Michels, V. V.; Pellikka, Patricia; Ballew, J. D.; Karst, M. L.; Herron, K. J.; Nelson, S. M.; Rodeheffer, R. J.; Olson, Timothy Mark.

In: Clinical Genetics, Vol. 74, No. 5, 2008, p. 445-454.

Research output: Contribution to journalArticle

Menon, S. C. ; Michels, V. V. ; Pellikka, Patricia ; Ballew, J. D. ; Karst, M. L. ; Herron, K. J. ; Nelson, S. M. ; Rodeheffer, R. J. ; Olson, Timothy Mark. / Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology. In: Clinical Genetics. 2008 ; Vol. 74, No. 5. pp. 445-454.
@article{5d0b2f173484454fba0734c8dcd4a2c2,
title = "Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology",
abstract = "We identified a unique family with autosomal dominant heart disease variably expressed as restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM), and sought to identify the molecular defect that triggered divergent remodeling pathways. Polymorphic DNA markers for nine sarcomeric genes for DCM and/ or HCM were tested for segregation with disease. Linkage to eight genes was excluded, but a cardiac troponin T (TNNT2) marker cosegregated with the disease phenotype. Sequencing of TNNT2 identified a heterozygous missense mutation resulting in an I79N substitution, inherited by all nine affected family members but by none of the six unaffected relatives. Mutation carriers were diagnosed with RCM (n = 2), non-obstructive HCM (n = 3), DCM (n = 2), mixed cardiomyopathy (n = 1), and mild concentric left ventricular hypertrophy (n = 1). Endomyocardial biopsy in the proband revealed non-specific fibrosis, myocyte hypertrophy, and no myofibrillar disarray. Restrictive Doppler filling patterns, atrial enlargement, and pulmonary hypertension were observed among family members regardless of cardiomyopathy subtype. Mutation of a sarcomeric protein gene can cause RCM, HCM, and DCM within the same family, underscoring the necessity of comprehensive morphological and physiological cardiac assessment in familial cardiomyopathy screening.",
keywords = "Dilated cardiomyopathy, Hypertrophic cardiomyopathy, Mutation, Restrictive cardiomyopathy, Sarcomere, TNNT2",
author = "Menon, {S. C.} and Michels, {V. V.} and Patricia Pellikka and Ballew, {J. D.} and Karst, {M. L.} and Herron, {K. J.} and Nelson, {S. M.} and Rodeheffer, {R. J.} and Olson, {Timothy Mark}",
year = "2008",
doi = "10.1111/j.1399-0004.2008.01062.x",
language = "English (US)",
volume = "74",
pages = "445--454",
journal = "Clinical Genetics",
issn = "0009-9163",
publisher = "Wiley-Blackwell",
number = "5",

}

TY - JOUR

T1 - Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology

AU - Menon, S. C.

AU - Michels, V. V.

AU - Pellikka, Patricia

AU - Ballew, J. D.

AU - Karst, M. L.

AU - Herron, K. J.

AU - Nelson, S. M.

AU - Rodeheffer, R. J.

AU - Olson, Timothy Mark

PY - 2008

Y1 - 2008

N2 - We identified a unique family with autosomal dominant heart disease variably expressed as restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM), and sought to identify the molecular defect that triggered divergent remodeling pathways. Polymorphic DNA markers for nine sarcomeric genes for DCM and/ or HCM were tested for segregation with disease. Linkage to eight genes was excluded, but a cardiac troponin T (TNNT2) marker cosegregated with the disease phenotype. Sequencing of TNNT2 identified a heterozygous missense mutation resulting in an I79N substitution, inherited by all nine affected family members but by none of the six unaffected relatives. Mutation carriers were diagnosed with RCM (n = 2), non-obstructive HCM (n = 3), DCM (n = 2), mixed cardiomyopathy (n = 1), and mild concentric left ventricular hypertrophy (n = 1). Endomyocardial biopsy in the proband revealed non-specific fibrosis, myocyte hypertrophy, and no myofibrillar disarray. Restrictive Doppler filling patterns, atrial enlargement, and pulmonary hypertension were observed among family members regardless of cardiomyopathy subtype. Mutation of a sarcomeric protein gene can cause RCM, HCM, and DCM within the same family, underscoring the necessity of comprehensive morphological and physiological cardiac assessment in familial cardiomyopathy screening.

AB - We identified a unique family with autosomal dominant heart disease variably expressed as restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM), and sought to identify the molecular defect that triggered divergent remodeling pathways. Polymorphic DNA markers for nine sarcomeric genes for DCM and/ or HCM were tested for segregation with disease. Linkage to eight genes was excluded, but a cardiac troponin T (TNNT2) marker cosegregated with the disease phenotype. Sequencing of TNNT2 identified a heterozygous missense mutation resulting in an I79N substitution, inherited by all nine affected family members but by none of the six unaffected relatives. Mutation carriers were diagnosed with RCM (n = 2), non-obstructive HCM (n = 3), DCM (n = 2), mixed cardiomyopathy (n = 1), and mild concentric left ventricular hypertrophy (n = 1). Endomyocardial biopsy in the proband revealed non-specific fibrosis, myocyte hypertrophy, and no myofibrillar disarray. Restrictive Doppler filling patterns, atrial enlargement, and pulmonary hypertension were observed among family members regardless of cardiomyopathy subtype. Mutation of a sarcomeric protein gene can cause RCM, HCM, and DCM within the same family, underscoring the necessity of comprehensive morphological and physiological cardiac assessment in familial cardiomyopathy screening.

KW - Dilated cardiomyopathy

KW - Hypertrophic cardiomyopathy

KW - Mutation

KW - Restrictive cardiomyopathy

KW - Sarcomere

KW - TNNT2

UR - http://www.scopus.com/inward/record.url?scp=53949106057&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=53949106057&partnerID=8YFLogxK

U2 - 10.1111/j.1399-0004.2008.01062.x

DO - 10.1111/j.1399-0004.2008.01062.x

M3 - Article

C2 - 18651846

AN - SCOPUS:53949106057

VL - 74

SP - 445

EP - 454

JO - Clinical Genetics

JF - Clinical Genetics

SN - 0009-9163

IS - 5

ER -