Cardiovascular Journal of Africa: Vol 26 No 2 (March/April 2015)

23 / 67

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 26, No 2, March/April 2015 AFRICA 69
of the myofilament.19,20 Although it is not clear how this affects
cross-bridge cycling and sarcomere energetics, some experiments
suggest that these mutations are thought to weaken the ability
of the cardiac troponin complex to fully inhibit the cross-bridge
attachment during the relaxation phase of muscle contraction,21–23
consequently reducing the rate of relaxation. Higher energy use
observed in transgenic models of HCM at a whole-cell or whole-
animal level may relate to a shift in Ca++ homeostasis (or other
changes) with higher energy costs to return the cells to their
pre-contractile basal state.
Conclusion
In the current investigation, we have demonstrated the usefulness
of HRM analysis for the identification of HCM-causing
mutations. The mutations identified here will now be used for
pre-symptomatic genetic screening of additional family members
to identify individuals at risk. Furthermore, new patients with
similar clinical features could also initially be screened for these
mutations.
Research studies often do not recount diagnostic disparities,
which could be a result of high incidence of disease, diagnostic
sophistication and personal interests. The ‘wrong’ diagnoses
of cor pulmonale, CP and TB pleuritis highlight the influence
of the high prevalence of TB in South Africa in making
a diagnosis. Furthermore, this study provides insight into
diagnostic disparities and processes that led to inappropriate
diagnosis in two individuals.
This work was supported by the Wellcome Trust (International Senior
Research Fellowship, fellowship GR073610MA to Hanlie Moolman-Smook),
London, United Kingdom. We thank all the participants involved in this
study and Mrs Ina le Roux for her technical assistance.
References
1. Van den Wijngaard A, Volders P, Van Tintelen JP, Jongbloed JD, van den
Berg MP, Lekanne Deprez RH, et al. Recurrent and founder mutations in
the Netherlands: cardiac troponin I (TNNI3) gene mutations as a cause of
severe forms of hypertrophic and restrictive cardiomyopathy. Neth Heart
J 2011; 19: 344–351.
2. Mogensen J, Kubo T, Duque M, Uribe W, Shaw A, Murphy R, et al.
Idiopathic restrictive cardiomyopathy is part of the clinical expression of
cardiac troponin I mutations. J Clin Invest 2003; 111: 209–216.
3. Kaski JP, Syrris P, Burch M, Tome-Esteban MT, Fenton M, Christiansen
M, et al. Idiopathic restrictive cardiomyopathy in children is caused by
mutations in cardiac sarcomere protein genes. Heart 2008; 94: 1478–1484.
4. Willott RH, Gomes AV, Chang AN, Parvatiyar MS, Pinto JR, Potter JD.
Mutations in Troponin that cause HCM, DCM AND RCM: what can we
learn about thin filament function? J Mol Cell Cardiol 2010; 48: 882–892.
5. Nagueh SF, Bierig SM, Budoff MJ, Desai M, Dilsizian V, Eidem B,
et al. American Society of Echocardiography clinical recommenda-
tions for multimodality cardiovascular imaging of patients with hyper-
trophic cardiomyopathy: Endorsed by the American Society of Nuclear
Cardiology, Society for Cardiovascular Magnetic Resonance, and Society
of Cardiovascular Computed Tomography. J Am Soc Echocardiogr 2011;
24: 473–498.
6. Corfield VA, Moolman JC, Martell R, Brink PA. Polymerase chain reac-
tion-based detection of MN blood group-specific sequences in the human
genome. Transfusion 1993; 33: 119–124.
7. Hall TA. BioEdit: a user-friendly biological sequence alignment editor and
analysis program for Windows 95/98/NT. Nucleic Acids Symp Ser 1999;
41: 95–98.
8. Wyndham CH. Mortality trends in the populations of the RSA from
causes commonly observed in developing communities, 1968-1977. S Afr
Med J 1984; 66: 945–950.
9. Mogensen J, Murphy RT, Kubo T, Bahl A, Moon JC, Klausen IC, et al.
Frequency and clinical expression of cardiac troponin I mutations in 748
consecutive families with hypertrophic cardiomyopathy. J Am Coll Cardiol
2004; 44: 2315–2325.
10. Niimura H, Patton KK, McKenna WJ, Soults J, Maron BJ, Seidman JG,
et al. Sarcomere protein gene mutations in hypertrophic cardiomyopathy
of the elderly. Circulation 2002; 105: 446–451.
11. Gruner C, Care M, Siminovitch K, Moravsky G, Wigle ED, Woo A, et
al. Sarcomere protein gene mutations in patients with apical hypertrophic
cardiomyopathy. Circ Cardiovasc Genet 2011; 4: 288–295.
12. Moon JC, Mogensen J, Elliott PM, Smith GC, Elkington AG, Prasad
SK, et al. Myocardial late gadolinium enhancement cardiovascular
magnetic resonance in hypertrophic cardiomyopathy caused by mutations
in troponin I. Heart 2005; 91: 1036–1040.
13. Kaski JP, Syrris P, Esteban MT, Jenkins S, Pantazis A, Deanfield JE,
et al. Prevalence of sarcomere protein gene mutations in preadolescent
children with hypertrophic cardiomyopathy. Circ Cardiovasc Genet 2009;
2: 436–441.
14. Ohtsuki I, Morimoto S. Troponin: regulatory function and disorders.
Biochem Biophys Res Commun 2008; 369 : 62–73.
15. Jurcut R, Giusca S, La GA, Vasile S, Ginghina C, Voigt JU. The echo-
cardiographic assessment of the right ventricle: what to do in 2010? Eur J
Echocardiogr 2010; 11: 81–96.
16. Kawut SM, Barr RG, Lima JA, Praestgaard A, Johnson WC, Chahal H,
et al. Right ventricular structure is associated with the risk of heart fail-
ure and cardiovascular death: the Multi-Ethnic Study of Atherosclerosis
(MESA) – right ventricle study. Circulation 2012; 126: 1681–1688.
17. Perry SV. Troponin I: inhibitor or facilitator. Mol Cell Biochem 1999; 190 :
9–32.
18. Syska H, Wilkinson JM, Grand RJ, Perry SV. The relationship between
biological activity and primary structure of troponin I from white skeletal
muscle of the rabbit. Biochem J 1976; 153 : 375–387.
19. Watkins H, Ashrafian H, McKenna WJ. The genetics of hypertrophic
cardiomyopathy: Teare redux. Heart 2008; 94: 1264–1268.
20. Gomes AV, Liang J, Potter JD. Mutations in human cardiac troponin I that
are associated with restrictive cardiomyopathy affect basal ATPase activity
and the calcium sensitivity of force development. J Biol Chem 2005; 280 :
30909–30915.
21. Wen Y, Pinto JR, Gomes AV, Xu Y, Wang Y, Wang Y, et al. Functional
consequences of the human cardiac troponin I hypertrophic cardio-
myopathy mutation R145G in transgenic mice. J Biol Chem 2008; 283 :
20484–20494.
22. Lang R, Gomes AV, Zhao J, Housmans PR, Miller T, Potter JD. Functional
analysis of a troponin I (R145G) mutation associated with familial hyper-
trophic cardiomyopathy. J Biol Chem 2002; 277: 11670–11678.
23. Elliott K, Watkins H, Redwood CS. Altered regulatory properties of
human cardiac troponin I mutants that cause hypertrophic cardiomyopa-
thy. J Biol Chem 2000; 275 : 22069–22074.