Document Type : Original Article
Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran ;Department of Molecular Medicine and Genetics, School of Medicine, Hamadan University of Medical Sciences, Hamadan,
Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Pompe disease (PD) is a progressive neuromuscular disorder that is caused by glucosidase acid alpha (GAA) deleterious mutations. Mitochondrial involvement is an important contributor to neuromuscular diseases. In this study the sequence of MT-ATP 6/8 and Cytochrome C oxidase I/II genes along with the expression levels of the former genes were compared in classic and non-classic patients.
Materials and Methods
In this case-control study, the sequence of MT-ATP 6/8 and Cytochrome C oxidase was analyzed by polymerase chain reaction (PCR)-Sanger sequencing and expression of MT-ATP genes were quantified by real time-PCR (RT-PCR) in 28 Pompe patients. The results were then compared with 100 controls. All sequences were compared with the revised Cambridge reference sequence as reference.
Screening of MT-ATP6/8 resulted in the identification of three novel variants, namely T9117A, A8456C and A8524C. There was a significant decrease in MT-ATP6 expression between classic (i.e. adult) and control groups (P=0.030). Additionally, the MT-ATP8 expression was significantly decreased in classic (P=0.004) and non-classic (i.e. infant) patients (P=0.013). In total, 22 variants were observed in Cytochrome C oxidase, five of which were non- synonymous, one leading to a stop codon and another (C9227G) being a novel heteroplasmic variant. The A8302G in the lysine tRNA gene was found in two brothers in a pedigree, while a T7572C variant in the aspartate tRNA gene was observed in two brothers in another pedigree.
The extent of mitochondrial involvement in the classic group was more significant than in the non-classic form. Beside GAA deleterious mutations, it seems that mtDNA variants have a secondary effect on PD. Understanding, the role of mitochondria in the pathogenesis of Pompe may potentially be helpful in developing new therapeutic strategies.