Consequences of Mutations in Genes Encoding Cardiac Troponin C, T and I – Molecular Insights (Pathophysiology and Genetics of Cardiomyopathies) Part 4

What we can learn from patients with troponin mutations

What can we learn from the patients with troponin mutations? One important message to the clinicians is that the risk of sudden cardiac death does not go along with the severity of left ventricular hypertrophy/wall thickness. Furthermore, sudden cardiac death may occur in all age groups with troponin mutations. These observations imply that other mechanisms than ischemia-triggered rhythm disturbances may account for the excessive risk of sudden cardiac death in this subgroup (and other subgroups?) of patients with HCM. In transgenic mice expressing the TnT-I79N (Ile79Asn) mutation, no ventricular hypertrophy or fibrosis was detected, but ventricular ectopy and the rate of stress-induced ventricular tachycardia were significantly increased (Knollmann et al, 2003). Baudenbacher et al. (2008) showed in this mouse model that the risk of developing ventricular tachycardia appears to be directly proportional to the degree of Ca2+ sensitization caused by different troponin T mutations (TnT-I79N, TnT-F110I, and TnT-R278C). They gave first evidence that reduction of Ca2+ -sensitivity (by blebbistatin) in myofilaments acts "antiarrhythmic". This work by Baudenbacher and coworkers clearly demonstrates that changes in the intracellular Ca2+ -sensor cardiac troponin are associated with arrhythmias, and histological/anatomical changes which do often later develop in the course of hypertrophic cardiomyopathy, are not a prerequisite for these life-threatening arrhythmias. In our laboratory, we studied the effects of the cTnI-R145G mutation on adrenergic signalling in isolated rat ventricular cardiomyocytes (Reis et al., 2008). This mutation hinders the transduction of the phosphorylation signal from troponin to the thin filament. Upon adrenergic stimulation of the cardiomyocytes, rates of shortening and relengthening were significantly suppressed.


This suppression was evident in response to 62- but not 61-adrenergic stimulation. These data demonstrate that adrenoceptor-mediated signalling may be altered by troponin mutations. Since sudden cardiac death in patients with HCM often occurs during exercise or physical activity, thus conditions with increased sympathetic activity, altered adrenergic signalling may be a potential player in the pathogenesis of life-threatening arrhythmias. Many other mechanism are currently under investigation, including the role of the myocyte enhancer factor 2, transforming growth factor, connective tissue factor, and periostin in the development of hypertrophy, diastolic dysfunction, and myocardial scarring (Seidman & Seidman, 2011); also altered intracellular calcium handling and abnormalities in myocardial energetics are under discussion to participate in this complex phenotype (Ho, 2010a,b). Despite obvious progress, the precise link between the molecular defect and the complex phenotype HCM is still not understood.

Patients/ Family

Clinical Presentation

Age/Sex

Septum (mm)

Wall (mm)

LVH type+

ECG

CHF

Prognosis

References

Ser69Phe

n=1 (9

unrelated SCD) Area: U.K.

29 M

n.a.

n.a.

n.a.

n.a.

n.a.

SCD

Varnava et al., 2001

Pro77Leu

n=1 (9

unrelated SCD) Area: U.K.

37 M

n.a.

n.a.

n.a.

n.a.

n.a.

SCD

Varnava et al., 2001

Ile79Asn

n=9 (1 family + unrelated p.) Area: multi-

n.a.

 tmp31-1

n.a.

n.a.

n.a.

n.a.

4 SCD in family

Watkins et al., 1995

ethnic/racial

n=1 (9

unrelated SCD) Area: U.K.

16 M

n.a.

n.a.

n.a.

n.a.

n.a.

SCD

Varnava et al., 2001

n=9 (1 family) Area: U.S.A.

50 F1

n.a.

n.a.

n.a.

n.a.

+

DCM, death at age 64

Menon et al., 2008

68 F

10

9

normal

+

+

DCM, death at age 73

66 F1

18

10

n.a.

+

+

-

46 M1

16

12

n.a.

+

+

mixed DCM/HCM

58 M1

12

10

normal

+

+

RCM type

53 F1

14

11

n.a.

+

+

RCM type

49 F1

16

9

n.a.

+

+

-

40 F1

24

8

n.a.

+

+

-

48 F

14

10

n.a.

-

-

-

Patients/ Family

Clinical Presentation

Age/Sex

Septum (mm)

Wall (mm)

LVH type+

ECG

CHF

Prognosis

References

Asp86Ala

n=1(389 unrelated p.) Area: U.S.A. Phe87Leu

39 M

n.a.

30

n.a.

n.a.

+

-

Van Driest et al., 2003

n=7 (1 family) Area: Spain

52 F

14

n.a.

n.a.

+

+

SCD in family

Gimeno et al., 2009

39 M

13

n.a.

n.a.

+

+

"

40 F

14

n.a.

n.a.

+

+

", ICD

30 F

18

n.a.

n.a.

+

+

", ICD

30 M

27

n.a.

n.a.

+

-

"

29 F

25

n.a.

n.a.

+

+

"

9 M

12

n.a.

n.a.

+

-

"

Arg92Gln

n=1 (150 unrelated p.) Area: Toscana

23 M

29

n.a.

III

+

-

-

Thierfelder et

al., 1994; Torricelli et al., 2003

n=32 (3 families + unrelated p.)

n.a.

n.a.

 tmp31-2

n.a.

n.a.

n.a.

SCD in 11 p

Watkins et al., 1995

Area : multi-

ethnic/racial

Arg92Trp n=18 (2 families) Area: South Africa

56 F

14

12

n.a.

+

n.a.

SCD in family

Moolman et al., 1997

57 F

13

12

n.a.

+

n.a.

41 F

12

13

n.a.

+

n.a.

28 F

24

11

n.a.

+

n.a.

35 F

13.8

7.5

n.a.

-

n.a.

23 F

6

6

-

+

n.a.

21 M

normal

normal

-

+

n.a.

38 M

9

9

-

+

n.a.

35 F

8

8

-

+

n.a.

28 M

7

8

-

+

n.a.

47 F

7

7

-

-

n.a.

27 F

6

6

-

-

n.a.

9 F

4

4

-

-

n.a.

28 M

8.5

8.5

-

-

n.a.

15 F

5

5

-

-

n.a.

11 F

7

7

-

-

n.a.

34 F

18-20

11

n.a.

+

n.a.

56 F

8

7

-

+

n.a.

n=1 (389 unrelated p.) Area : U.S.A.

27 F

n.a.

32

n.a.

n.a.

-

-

Van Driest et al., 2003

n=2(9

unrelated SCD) Area.U.K.

22 M

n.a.

n.a..

n.a.

n.a.

n.a.

SCD

Varnava et al., 2001

6 F

n.a.

n.a.

n.a.

n.a.

+

transplant

Patients/ Family

Clinical Presentation

Prognosis

References

Age/Sex

Septum (mm)

Wall

(mm)

LVH type+

ECG

CHF

Arg92Leu

n=1 (9

unrelated SCD) Area: U.K.

26 M

n.a.

n.a.

n.a.

n.a.

n.a.

SCD

Varnava et al., 2001

n=4 (1 family) Area: France

43 F

n.a.

19

n.a.

+

CHF at 44 y

Forissier et al., 1996

Varnava et al., 2001

23 M

n.a.

35

n.a.

+

+

n.a

20 F

n.a.

n.a.

apical

+

+

n.a.

45 F

n.a.

10

n.a.

+

-

n.a.

Arg94Leu

n=2 (9

unrelated SCD) Area: U.K.

17 M

n.a.

n.a.

n.a.

n.a.

n.a.

SCD

Ala104Val

n=4 (1 family) Area: Japan

21 F

n.a.

n.a.

n.a.

n.a.

n.a.

SCD

50 F

15

8

n.a.

+

+

SCD at age 50

Nakajima-Taniguchi et al., 1997

36 F

17

6

n.a.

+

+

SCD at age 36 ventricular tachycardia

54 F

17

8

n.a.

+

+

33 F

20

12

n.a.

+

-

-

Phe110Ile

n=2 (1 family) Area : multiethnic/racial n=16 (6

families) Area : Japan

n.a.

n.a.

17 (n=2)

n.a.

n.a.

n.a.

Watkins et al., 1995

38 F

27

17

III

+

Anan et al., 1998

69 F

22

14

III

+

-

SCD in family

47 F

20

13

III

+

-

SCD in family

87 F

9

9

IV

+

-

-

48 M

10

10

IV

+

-

-

42 F

11

11

normal

-

-

-

64 M

23

10

II

+

-

-

70 M

20

11

II

+

-

-

47 F

13

13

III

+

-

-

45 M

12

10

normal

+

-

-

39 F

13

13

III

+

-

-

24 F

11

11

IV

+

-

-

56 F

19

11

II

+

-

SCD in family

53 M

15

13

III

+

-

31 F

21

12

II

+

-

28 F

10

10

normal

+

-

"

Phe110Val

n=3 (150 unrelated p.) Area: Italy

28 F

32

n.a.

III

+

-

-

Torricelli et al., 2003

48 F

21

n.a.

III

+

n.a.

-

82 M

15

n.a.

II

+

n.a.

-

Patients/ Family

Clinical Presentation

Age/Sex

Septum (mm)

Wall (mm)

LVH type+

ECG

CHF

Prognosis

References

Lys124Asn

n=1 (71 unrelated p.) Area : China Arg130Cys n=2 (150 unrelated p.) Area: Italy

41 F

n.a.

n.a.

LVH

n.a.

n.a.

-

An et al., 2004

55 M

23

n.a.

III

+

Torricelli et al., 2003

58 F

13

n.a.

n.a.

+

Glu160

n=32 (2 families +unrelated p.) Area : multiethnic/racial n=2 (150 unrelated p.) Area: Italy

n.a.

n.a.

 tmp31-3

n.a.

n.a.

n.a.

SCD in 14

Watkins et al., 1995

50 F

20

n.a.

III

+

-

-

Torricelli et al., 2203

55 M

22

n.a.

III

+

+

-

Watkins et al., 1995

Glu163Lys

n=5(1 family + unrelated p.) Area. multiethnic/racial Ser179Phe n=1 (1 family) Area: Kuwait

n.a.

n.a.

 tmp31-4

n.a.

n.a.

n.a.

SCD in 0

17 M

25

11

n.a

+

-

SCD

Ho et al., 2000

Glu244Asp

n=1 (1 family) Area: multiethnic/racial Lys247Arg n=1 (30 unrelated p.) Area: Spain

n.a.

n.a.

n.a.

n.a.

n.a.

n.a.

SCD in 0

Watkins et al., 1995

60 F

23

n.a.

n.a.

n.a.

n.a.

-

Garcia-Castro et al., 2003
tmp31-5

n.a.

n.a.

 tmp31-6

n.a.

n.a.

n.a.

SCD in 9

Watkins et al., 1995

15 M

n.a.

n.a.

n.a.

n.a.

n.a.

SCD

Varnava et al., 2001

Asn271Ile

3 (1 family) Area: Spain

62 M

22

n.a.

n.a.

+

-

-

Gimeno et al., 2009

36 M

14

n.a.

n.a.

+

-

-

31 F

9

n.a.

n.a.

-

-

-

Patients/ Family

Age/Sex

Septum (mm)

Clinical Presentation

Prognosis

References

Wall (mm)

LVH type+

ECG

CHF

Lys273Glu

n=8 (2 families) Area: Japan

58 F

7

8

n.a.

n.a.

n.a.

DCM features

Fujino et al., 2002

32 F

23

7

asym.

n.a.

n.a

-

29 F

23

10

asym.

n.a.

n.a.

-

75 F

15

13

n.a.

n.a.

n.a.

SCD in family

78 F

15

11

asym.

n.a.

n.a.

"

75 F

16

9

asym.

n.a.

n.a.

"

49 F

20

9

asym

n.a.

n.a.

"

46 M

21

10

asym

n.a.

n.a.

"

Arg278Cys

n=3 (1 family + unrelated p.) Area: multiethnic/racial n=3(389 unrelated p.) Area: U.S.A.

n.a.

n.a.

 tmp31-7

n.a.

n.a.

n.a.

SCD in 1

Watkins et al., 1995

57 M

n.a.

20

n.a.

n.a.

-

-

Van Driest et al.,, 2003

66 M

n.a.

15

n.a.

n.a.

+

pacemaker

74 M

n.a.

23

n.a.

n.a.

+

TASH

n=1 Area: U.K.

57 M

12

n.a.

n.a.

+

+

late onset HCM

Elliott et al., 1999

n=1 (30 unrelated p.)

60 F

22

n.a.

n.a.

n.a.

n.a.

Garcia-Castro et al., 2003

Area: Spain

55 F

22

n.a.

n.a.

+

+

-

n=8 (2 families) Area: Spain

Gimeno et al., 2009

59 M

22

n.a.

n.a.

+

+

-

27 M

12

n.a.

n.a.

-

-

-

30 M

10

n.a.

n.a.

-

-

-

29 M

10

n.a.

n.a.

-

-

-

21 M

40

n.a.

n.a.

+

+

ICD-Impl.

64 M

26

n.a.

n.a.

+

-

-

33 M

11

n.a.

n.a.

+

-

-

n=6 (2 families) Area: Greek

40 M

20

11

asym

+

+

SCD in family

Theopistou et al., 2004

71 F

13

12

conc.

+

+

"

41 M

10

8

normal

-

n.a.

"

38 M

10

10

normal

-

n.a.

"

14 F

7

8

normal

-

n.a.

"

13 M

22

11

asym.

+

-

SCD age 15

n=1 (150 unrelated p.) Area: Italy

66 M

24

n.a.

III

+

+

-

Torricelli et al., 2003

Patients/ Family

Age/Sex

Septum (mm)

Clinical Presentation

Prognosis

References

Wall (mm)

LVH type+

ECG

CHF

Arg278Pro

n=1 (389 unrelated p.) Area: U.S.A. n=1 (143 unrelated p.) Area : Greek

47 M

n.a.

19

n.a.

n.a.

+

ICD

Van Driest et al., 2003

18 M

n.a.

n.a.

LVH

n.a.

n.a.

-

Miliou et al., 2005

Arg286Cys

n=1 (143 unrelated p.) Area : Greek

26 F

n.a.

n.a.

LVH

n.a.

n.a.

-

Miliou et al., 2005

Arg286His

n=2 (389 unrelated p.) Area: U.S.A.

49 M

n.a.

20

n.a.

n.a.

-

-

Van Driest et al., 2003

39 M

n.a.

25

n.a.

n.a.

+

myectomy

Table 4. Mutations in the TNNT2 Gene Associated with HCM

Number of affected patients is given (out of a group of unrelated HCM patients or families with HCM). Age=age at investigation if not otherwise noted; 1age at diagnosis; n.a.=data not available; SCD=sudden cardiac death; DCM=dilated cardiomyopathy like-type; RCM=restrictive cardiomyopathy like-type; CHF=congestive heart failure; TASH=transcoronary septal ablation; ICD=internal automated defibrillator; area=living area of study patients. +Left ventricular hypertrophy (LVH) is classified according to according to Maron et al. (1981) type I=confined to the anterior segment of the ventricular septum, type II=involved anterior and posterior septum, type III=involvement of both the septum and the free wall of the left ventricle, and type IV=regions other than the basal and anterior septum (e.g. apical area).

Clinical Presentation

Patients/Family

Age/Sex

Septum (mm)

Wall (mm)

LVH type+

ECG

CHF

Prognosis

Reference

Ala157Val

n=5 (3 families) Area : U.K. n=1 (1 family) Area: Portugal Arg162Gln n=7 (3 families) Area: U.K. n=2 (389 unrelated p.) Area: U.S.A.

n.a.

n.a.

n.a.

n.a.

+

n.a.

SCD in family

Mogensen et al., 2004

24 M

n.a.

n.a.

LVH

*

*

SCD at age 44

Brito & Madeira, 2005

n.a.

n.a.

n.a.

n.a.

n.a.

n.a

SCD in family

Mogensen et al., 2004

76 F

n.a.

17

n.a.

n.a.

+

myectomy

Van Driest et al., 2003

33 M

n.a.

19

n.a.

n.a.

+

SCD in family

n=3 (1 family) Area: Australia

70 M

n.a.

n.a.

n.a.

n.a.

n.a.

n.a.

Doolan et al., 2005

44 M

n.a.

10

normal

-

-

-

40 M

n.a.

10

normal

-

-

-

Arg162Pro

n=2 (1 family) Area: Australia

52 F

n.a.

9

normal.

-

-

-

Doolan et al., 2005

25 F

n.a.

14

n.a.

+

-

cardiac arrest at age 21

Ser166Phe

n=3 (389 unrelated p.) Area: U.S.A.

48 F

n.a.

22

n.a.

n.a.

+

myectomy

Van Driest et al., 2003

79 F

n.a.

14

n.a.

n.a.

+

myectomy

21 F

n.a.

17

n.a.

n.a.

+

myectomy

n=1 (1 family) Area: U.K.

n.a.

19

n.a.

n.a.

+

n.a

-

Mogensen et al., 2004

Lys183Glu

n=3 (1 family) Area: U.K.

n.a.

n.a.

n.a.

n.a.

+

n.a

-

Mogensen et al., 2004

Lys183del n=25 (7 families) Area: Japan

65 F

13

7

I/II

+

n.a.

SCD in family

Kokado et al., 2000

61 F

17

12

I/II

+

n.a.

51 F

9

10

normal

+

n.a.

46 F

20

10

I/II

+

n.a.

36 F

16

8

I/II

+

n.a.

48 F

7

7

normal

+

n.a.

36 M

18

13

III

+

n.a.

33 F

21

9

I/II

+

n.a.

47 F

10

8

normal

+

n.a.

27 F

13

9

III

+

n.a.

8 M

5

5

normal

-

n.a.

85 M

14

10

I/II

+

n.a.

56 F

23

11

IV

+

n.a.

48 F

13

14

IV

+

n.a.

71 F

11

10

normal

+

n.a.

Patients/Family

Age/Sex

Septum (mm)

Clinical Presentation

Prognosis

Reference

Wall (mm)

LVH type+

ECG

CHF

49 M

5

9

normal

+

n.a.

24 F

20

11

I/II

+

n.a.

23 F

9

8

normal

+

n.a.

66 F

11

11

normal

+

n.a.

62 M

13

12

normal

+

n.a.

35 M

12

11

normal

-

n.a.

48 M

10

13

LVH

+

n.a.

24 M

13

10

LVH

+

n.a.

68 F

19

11

I/II

+

n.a.

78 F

22

13

I/II

+

n.a.

Arg186Gln

n=5 ( 2 families) Area: U.K.

n.a.

n.a.

n.a.

n.a.

n.a.

n.a

SCD in family

Mogensen et al., 2004

Asp196Asn

n=4 (2 families) Area: U.K. n=1 with late-onset HCM Area: n.a.

n.a.

n.a.

n.a.

n.a.

+

n.a

-

Mogensen et al., 2004

>40

n.a.

LVH

+

+

n.a.

n.a.

Niimura et al., 2002

Leu198Pro

n=1 (1 family) Area: Australia

15 M

n.a.

22

n.a.

+

-

SCD at age 15

Doolan et al., 2005

Ser199Gly

n=1 (1 family) Area: U.K.

n.a.

n.a.

n.a.

apical

+

n.a.

-

Mogensen et al., 2004

Ser199Asn

n=8 (2 families) Area: U.K.

n.a.

n.a.

n.a.

n.a.

+

n.a.

SCD in family

Mogensen et al., 2004

n=1 (1 family) Area: Portugal

Glu202Gly

n=1 (1 family) Area: U.K.

52 M n.a.

n.a.

19

n.a. n.a.

LVH n.a.

+ +

n.a.

cardiac arrest at age 61

Brito & Madeira, 2005

Mogensen et al., 2004

Gly203Arg

n=2 (1 family) Area: U.K.

Gly203 frameshift

n.a.

n.a.

n.a.

n.a.

+

n.a.

-

Mogensen et al., 2004

n=4 (1 family) Area: Sweden

71 F

9

9

normal

+

+

-

Morner et al., 2000

61 M

15

8

LVH

+

-

-

64 M

16

14

LVH

+

-

-

27 F

8

7

normal

-

-

-

Arg204His

n=3 (1 family) Area: Australia

37 M

n.a.

17

n.a.

+

-

cardiac arrest at age 17

Doolan et al., 2005

9 M

n.a.

7

normal

+

-

-

5 M

n.a.

5

normal

+

-

-

Table 5. Mutations in the TNNI3 Gene Associated with HCM

Patients/ Family

Age/Sex

Septum (mm)

Clinical Presentation

Prognosis

Reference

Wall (mm)

LVH type+

ECG

CHF

Ala8Val

n=1 (1025 unrelated p.) Area: U.S.A./ Caucasian

37M

18

n.. a

n.a.

n.a.

+

myectomy

Landstrom et al., 2008

Leu29Gln n=1 Area: Germany

60 M

15

15

n.a.

+

+

n.a.

Hoffmann et al. ,2001

Cys84Tyr n=1 (1025 unrelated p.) Area: U.S.A./ Caucasian

17 M

19

n.a.

n.a.

n.a.

-

n.a.

Landstrom et al., 2008

Glu134Asp n=1 (1015 unrelated p.) Area: U.S.A./ Caucasian

22 F

26

n.a.

n.a.

n.a.

+

myectomy

Landstrom et al., 2008

Asp145Glu n=1 (1025 unrelated p.) Area: U.S.A./ Caucasian

58 M

22

n.. a

n.a.

n.a.

+

myectomy

Landstrom et al., 2008

c.363dupG frameshift n=1(1 family) Area: U.S.A.

19 M

n.a.

n.a.

n.a.

n.a.

n.a.

SCD

Chung et al., 2011

Table 6. Mutations in the TNNC1 Gene Associated with HCM

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