Elsevier

Gene

Volume 506, Issue 2, 15 September 2012, Pages 339-343
Gene

Mitochondrial ND5 12338T>C variant is associated with maternally inherited hypertrophic cardiomyopathy in a Chinese pedigree

https://doi.org/10.1016/j.gene.2012.06.071Get rights and content

Abstract

Hypertrophic cardiomyopathy is a primary disorder characterized by asymmetric thickening of the septum and left ventricular wall, which affects 1 in 500 individuals in the general population. Mutations in mitochondrial DNA have been found to be one of the most important causes of hypertrophic cardiomyopathy. Here we report the clinical, genetic and molecular characterization of a Han Chinese family with a likely maternally transmitted hypertrophic cardiomyopathy. Four (2 men/2 women) of 5 matrilineal relatives in this 3-generation family exhibited the variable severity and age at onset of 44 to 79 years old. Sequence analysis of the entire mitochondrial DNA in this pedigree identified the known homoplasmic ND5 12338T>C variant. This mitochondrial DNA haplogroup belongs to the Eastern Asian F2a. The 12338T>C variant, highly evolutionarily conserved, resulted in the replacement of the translation initiating methionine with a threonine, shortening the ND5 polypeptide by 2 amino acids. The occurrence of ND5 12338T>C variant exclusively in maternal members of this Chinese family suggested that the 12338T>C variant is associated with maternally inherited hypertrophic cardiomyopathy. Our findings will provide theoretical basis for genetic counseling of maternally inherited hypertrophic cardiomyopathy.

Highlights

► A Chinese family with maternally transmitted hypertrophic cardiomyopathy (HCM) ► We reported the clinical, genetic and molecular characterization of this family. ► The mitochondrial ND5 12338T>C variant was first reported in the HCM population. ► The ND5 12338T>C variant was associated with maternally inherited HCM.

Introduction

Hypertrophic cardiomyopathy (HCM) is a primary disorder characterized by asymmetric thickening of the septum and left ventricular wall. In particular, HCM affects 1 in 500 individuals in the general population (Maron et al., 2006). HCM is the most common cause of sudden cardiac death in individuals aged less than 35 years, including competitive athletes (Maron et al., 1996). The pathogenesis of HCM remains poorly understood because of multi-factorial causes. HCM can be caused by a single gene or multi-factorial conditions, resulting from interactions between environmental and inherited risk factors. Of the hereditary factors, maternal transmission of HCM has been implicated in some pedigrees, suggesting that the mutation in mitochondrial DNA (mtDNA) is one of the molecular bases for this disorder (Hattori et al., 2005, Song et al., 2011). The first mtDNA point mutation was identified in the gene encoding tRNALeu(UUR) to be associated with HCM in 1991 (Zeviani et al., 1991). Since then, several mutations have been reported to be associated with HCM (Song et al., 2011). However, the molecular pathogenesis of hypertrophic cardiomyopathy in the Chinese population remains poorly understood.

In an effort to understand the role of the mitochondrial genome in the pathogenesis of HCM in the Chinese population, a systematic and extended mutational screening of mtDNA has been initiated in a cohort of HCM subjects at the Cardiovascular Clinic in the First Affiliated Hospital, Zhejiang University School of Medicine, China. In the present study, we performed clinical, genetic, and molecular characterizations of a Han Chinese family in which maternally transmitted HCM is suggested. Mutational analysis of the mitochondrial genome identified the ND5 12338T>C variant, which only occurred in the matrilineal relatives of this family and was absent in 151 age and sex matched control individuals. These findings suggest that the 12338T>C variant is involved in the pathogenesis of maternally inherited HCM in this Chinese pedigree.

Section snippets

Subjects

As a part of the genetic screening program for HCM, a Han Chinese family (Fig. 1) was recruited at the Cardiovascular Clinic in the First Affiliated Hospital, Zhejiang University School of Medicine, China. Informed consent, blood samples, and clinical evaluations were obtained from all of the participating family members, under protocols approved by the ethics committee of the First Affiliated Hospital, Zhejiang University School of Medicine, China. Members of this family were interviewed and

Clinical presentation

The clinical characteristics of the seven members (5 maternal members/2 non-maternal members) of the pedigree at presentation are summarized in Table 1. The proband (II-1) had electrocardiography (ECG) abnormality during his annual physical examination at age 44, and then was diagnosed as HCM by echocardiography (ECHO) without any symptoms. ECHO showed that the proband has 22 mm maximum left ventricular wall thickness (MLVWT), 18.7 mm interventricular septum (IVS) and 9.1 mm left posterior wall

Discussion

In the present study, we have performed the clinical, genetic, and molecular characterization of a Han Chinese pedigree with HCM. The HCM, as a sole clinical phenotype, was only present in the matrilineal relatives of this 3-generation pedigree. Clinical and genetic evaluations revealed the variable severity and age at onset in HCM. In the four affected matrilineal members, the MLVWT ranged from a slight hypertrophy of 13.5 mm to a significant hypertrophy of 30 mm, and the IVS thickness ranged

Conclusion

Our present investigations suggested that the 12338T>C variant should be added to the list of inherited risk factors for future molecular diagnosis of hypertrophic cardiomyopathy.

Acknowledgments

This work was supported by National Natural Science Foundation of China (No. 30971599), National Basic Research Program of China (Grant no. 2012CB966800), Program for New Century Excellent Talents in University (NCET-06-0526), Program for Science and Technology in Zhejiang Province (No. 2008C23028) and 151 Excellent Talents in Zhejiang Province (No. 06-2-008). We thank Dr. Immo E. Scheffler at UC San Diego for discussion and writing supports.

Ethics approval

This study was conducted with the

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These authors contributed equally to this work.

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