Elsevier

Mitochondrion

Volume 10, Issue 4, June 2010, Pages 330-334
Mitochondrion

Detection of eight frequently encountered point mutations in mitochondria in Chinese patients suggestive of mitochondrial encephalomyopathies

https://doi.org/10.1016/j.mito.2010.01.008Get rights and content

Abstract

To evaluate eight frequently encountered mitochondrial DNA (mtDNA) point mutations (A3243G, T8993G/C, A8344G, A1555G, G11778A, G3460A and T14484C) in Chinese, we recruited 1559 sporadic patients suspected of mitochondrial diseases and 206 family members. In suspected patients, 158 cases were detected with one of these eight mtDNA mutations (10.1%). A3243G was the most common mtDNA mutation both in suspected patients (9.4%) and in the relatives (34.2%). In addition, the ratios of A3243G (mutant/wild-type) and A8344G were significantly correlated with the patients’ age of examination. Moreover, in 76 unrelated probands, the ratio of A3243G was correlated well with their seizures and myopathies.

Introduction

Mitochondrial disorders have been attributed to nuclear genome and/or mitochondrial genome mutations which result in respiratory chain disturbances and subsequent oxidative phosphorylation dysfunctions. Most of the known mitochondrial diseases have been caused by mtDNA mutations, and many common molecular etiologies have been established. For example, mtDNA A3243G, T8993G/C, A8344G, A1555G, and G11778A, G3460A, T14484C mutations are associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh’s syndrome (LS), myoclonic epilepsy with ragged-red fibers (MERRF), aminoglycoside induced deafness (AID) and Leber’s hereditary optic neuropathy (LHON), respectively. However, the diagnosis of mitochondrial diseases is still a challenge to clinicians, since a variety of clinical manifestations may develop at any age, and may involve any tissue or organ, especially in high-energy demanding organs such as the skeletal muscle and nervous system. Moreover, heteroplasmy and threshold effect of mitochondrial mutations also contribute to the difficulties in clinical and genetic diagnosis for these diseases. At present, many consensus diagnostic criteria for mitochondrial diseases have been proposed, which include several molecular methods (Bernier et al., 2002, Wolf and Smeitink, 2002, Morava et al., 2006). Although hundreds of mtDNA mutations have been found in association with mitochondrial diseases during the last two decades, these eight point mutations mentioned above are of relatively high frequency. In this study, we aimed to evaluate the significance of the detection for eight frequent mtDNA point mutations from peripheral blood of Chinese patients suspected of mitochondrial diseases, and to correlate level of heteroplasmy with clinical presentations in patients with A3243G transition.

Section snippets

Subject

From October 2001 to March 2009, 1559 Chinese probands and 206 relatives were referred by neurologists and medical imaging specialists to the Central Laboratory at the Peking University First Hospital. Some of the patients in our previous report (Qi et al., 2007) were included in this study. In present study, those patients were initially suspected of having mitochondrial disease based on the presence of at least two of the following three criteria: (1) clinical manifestations suggesting the

Characteristics of the subjects

One thousand seven hundred and sixty five cases we tested consisted of 1559 sporadic patients and 206 family members from 23 provinces and cities in China, including Hebei province (13%), Henan province (12%), Shandong province (10%), Shanxi province (10%), and Beijing (9%). Most of the suspects showed elevated plasma lactate or pyruvate, and 43% of the patients showed abnormal brain MRI. Muscle weakness, seizures and developmental retardation were found in 35.6%, 36.2% and 28.3% of patients,

Discussion

This is the first large-scale investigation about eight common mtDNA point mutations in Chinese patients with suspected mitochondrial diseases. Here we reported the detection results for the mutations of mtDNA A3243G, T8993G/C, A8344G, A1555G, G11778A, G3460A and T14484C in 1559 suspects based on clinical, biochemical and image findings, and in 206 family members. In 1765 samples, the overall detection rate of eight mtDNA mutations was 12.9% (227 cases), indicating that mtDNA mutations are

Conclusions

In this study cohort, 12.9% cases carried one of the eight frequently encountered mtDNA point mutations, and A3243G was the most frequent mutation detected in the Chinese patients with MELAS. Additionally, our data confirmed that level of heteroplasmy of the A3243G mutation correlates with severity of clinical manifestations and age of patients. A general population screening from various ethnic groups rather than screening of clinically affected individuals in referral centers will be

Acknowledgments

We greatly acknowledge the related physicians, patients and their family members for their collaboration in this investigation. This study was financially supported by grants from National Natural Science Foundation of China (No. 30700912).

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    The first four authors contribute equally to this paper.

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