MT-CYB sequencing analysis in frontotemporal lobar degeneration

Abstract

Frontotemporal lobar degeneration (FTLD) is the second most common cause for dementia before 65 years of age. FTLD comprises variants with a very diverging spectrum, regarding the clinical presentation, genetic features, and neuropathology. In the last decades remarkable progresses have been achieved in terms of genetic causes and their relation with neuropathology. Given the complexity of this disease, several aetiologies have been proposed. One of the theories includes variations in mitochondrial DNA (mtDNA) that affect the energy production in mitochondrial respiratory chain and consequently affect the tissue with higher energy demands, the central nervous system. The aim of our study is to identify variations of MT-CYB gene in 70 DNA samples of patients with probable diagnosis of FTLD. Total DNA of the samples was extracted from peripheral blood and MT-CYB gene was analysed and the sequence variations found were submitted to an in silico analysis. A total of 37 different sequence variations were identified in 44 patients (63%): 22 are synonymous, 2 are novel variations (m.15073C>T; m.15127C>T) that have not been reported to date in MITOMAP database and 15 are non-synonymous. The results of the in silico analysis suggested that 3 variations may be pathogenic: m.14927A>C affects protein function according to SIFT and the amino acid is conserved in all mammals; m.15164T>C is predicted to be deleterious by Provean, it is an alteration in a critical position and is totally conserved in all species studied, and m.15465T>C affects protein function according to Poly-Phen and SIFT and is highly conserved in mammals. Further investigation is important to clarify a possible relationship between mtDNA variations and pathophysiology of FTLD. However, our study represents a significant improvement in the complex field of dementia such like FTLD