Wild-Type Mitochondrial DNA Copy Number in Urinary Cells as a Useful Marker for Diagnosing Severity of the Mitochondrial Diseases

Hui Liu,Ying Zhang,Liwen Wang,Lin Li,Yufeng Xu,Yu Qi,Hairong Wu,Yanyan Cao,Fang Fang,Yanling Yang,Pei Pei,Yinan Ma,Yang Xiao,Songtao Wang,Hong Pan,Xuefei Zheng,Liping Zou,Sainan Zhu,Yidong Bai

doi:10.1371/journal.pone.0067146

Abstract

The genotype-phenotype relationship in diseases with mtDNA point mutations is still elusive. The maintenance of wild-type mtDNA copy number is essential to the normal mitochondrial oxidative function. This study examined the relationship between mtDNA copy number in blood and urine and disease severity of the patients harboring A3243G mutation. We recruited 115 A3243G patients, in which 28 were asymptomatic, 42 were oligo-symptomatic, and 45 were poly-symptomatic. Increase of total mtDNA copy number without correlation to the proportion of mutant mtDNA was found in the A3243G patients. Correlation analyses revealed that wild-type mtDNA copy number in urine was the most important factor correlated to disease severity, followed by proportion of mutant mtDNA in urine and proportion of mutant mtDNA in blood. Wild-type copy number in urine negatively correlated to the frequencies of several major symptoms including seizures, myopathy, learning disability, headache and stroke, but positively correlated to the frequencies of hearing loss and diabetes. Besides proportion of mutant mtDNA in urine, wild-type copy number in urine is also an important marker for disease severity of A3243G patients.

Highlights

The A3243G mutation in mitochondrial DNA is at a relatively high frequency of prevalence in population, and is associated with a wide spectrum of clinical manifestations [1,2]
We found that wild-type mitochondrial DNA (mtDNA) copy number in urine was the most important factor relating to disease severity, followed by proportion of mutant mtDNA in urine and proportion of mutant mtDNA in blood
Decrease of wild-type mtDNA copy number in urine and increase of proportion of mutant mtDNA in urine and blood were often associated with the increase of disease severity in A3243G patients, indicating that wild-type mtDNA copy number in urine is an important marker for disease severity of A3243G patients

Summary

Introduction

The A3243G mutation in mitochondrial DNA (mtDNA) is at a relatively high frequency of prevalence in population, and is associated with a wide spectrum of clinical manifestations [1,2]. The proportion of mutant mtDNA is considered to be a determinant factor for the phenotype of the disease [3]. This conclusion is still in a matter of debate [4,5]. Several studies have substantiated that the total mtDNA copy number plays a role in the phenotype of mitochondrial encephalomyopathies caused by mtDNA point mutations [6,7]. We performed a study to reveal wild-type mtDNA copy number in urine and blood in relation to disease severity and frequency of clinical symptoms in patients with A3243G mtDNA mutation

Methods

Results

Conclusion