Haplogroup distribution and Polymorphism in the non-coding region of human Mitochondrial DNA in patients harboring the primary G11778A, G3460A, T14484C mutations

Leber hereditary optic neuropathy (LHON) is a maternally inherited form of retinal ganglion cell degeneration leading to optic atrophy in young adults. It is caused by three primary point mutations including G11778A, G3460A, and T14484C in the mitochondrial genome (mtDNA). These three mutations account for the majority of LHON cases and they affect genes that encode for different subunits of mitochondrial complex I. Human mitochondrial DNA (mtDNA) is double-stranded closed circular molecule present 1000-10000 copies per cell. Objectives: In order to identify polymorphic sites, genetic background and also to find out any possible association between LHON primary mutations and mtDNA haplogroups (hg), the complete non-coding region of mitochondrial DNA from 30 unrelated LHON patients harboring one of the primary mutations was sequenced. Methods: Alignment were made with the Revised Cambridge Reference Sequence (rCRS) and any differences recorded as single base substitution (SBS), numerical changes in C-tract (PCT), insertions and deletions. Results: Our results showed that majority of our patients belonged to hg J, T and HV rather than hgs U3, U4, U5 and W, which found only in two patients. (6%) As compared to insertions and deletions, nucleotide substitutions make up the majority of the mutations. (94.5%) We have predominantly found transitions (79.2%) and a significantly lower frequency of transvertions (15.3%) whereas insertions (5.5%) as well as deletions (0%) are rather rare. Ten polymorphisms were newly identified in this study not published in the mitomap database. Also PCT changes were present in all of our samples. Conclusions: The analysis presented here for the first time provides evidence that there is association between G3460A with hg W.

کلیدواژه ها:

MtDNA ، LHON ، Haplogroup ، D-loop