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Abstract. The present study investigates the spectrum and incidence of mitochondrial DNA (mtDNA) mutations associated with Leber's hereditary optic neuropathy (LHON) in a Han population using a multi-gene panel with 46 LHON-associated mutations among 13 mitochondrial genes. A total of 23 mutations were observed in a cohort of 275 patients and 281 control subjects using multi-gene panel analysis IntroductionLeber's hereditary optic neuropathy (LHON; OMIM 535000) is a classic mitochondrial disease, associated with a rapid, painless, acute or sub-acute bilateral visual loss in young adults, predominantly caused by the primary and secondary mutations in mitochondrial DNA (mtDNA). It has been reported that 1:8,500 individuals harbor a primary LHON-causing mutation and 1:31,000 experience visual loss as a result of LHON in the North East of England (1). Few significant improvements in visual acuity are reported following atrophy of the optic discs. LHON typically affects males more frequently than females, with the incomplete and variable penetrance estimated at ~50% in males and 10% in females (2-4). Additionally, certain LHON cases have additional clinical symptoms, such as movement disorders, dystonia, and multiple-sclerosis-like illness, which complicate the diagnosis in the clinical setting (5-7). Although the majority ofcases of LHON transmitted by maternal inheritance have a history of visual loss in families, up to 40% of cases are sporadic (5).The genetic cause of LHON is mutations in the mitochondrial genome, which is a double-stranded 16,569-nucleotide pair, circular molecule, consisting of one D-Loop region and 37 genes. The three most causative mutations, m.11778G>A (M T-ND4), m.14484T>C (M T-ND6) and m.3460G>A (MT-ND1), have been reported to account for 90% of LHON patients in a Caucasian population, but for only 38.3 and 46.5% of cases in two large cohorts of Chinese Han subjects with LHON (7-10). Our previous studies have shown the spectrum of genes, MT-ND1, MT-ND4 and MT-ND6, and the frequency of the three primary mutations in a Chinese LHON population (8-10) using Sanger sequencing. In addition, secondary mutations that contributed to the high penetrance,

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We investigated the role of mitochondrial genetic alterations in hepatocellular carcinoma by directly comparing the mitochondrial genomes of 86 matched pairs of HCC and non-tumor liver samples. Substitutions in 637 mtDNA sites were detected, comprising 89.80% transitions and 6.60% transversions. Forty-six somatic variants, including 15 novel mutations, were identified in 40.70% of tumor tissues. Of those, 21 were located in the non-coding region and 25 in the protein-coding region. Twenty-two somatic nonsynonymous changes were identified as putative pathogenic variants, including 4 truncating mutations produced by three frameshifts (MT-ATP6 8628 insC; MT-ND5 13475 T-del, and MT-CYB 14984 insA) and 1 nonsense mutation in MT-CO3 9253 G>A. Among the somatic variants, only m.13676 A>G (MT-ND5), found in only 1 tumor, was heteroplasmic. Both inherited and somatic variants were predominately located in the D-loop region and the MT-ND5 gene. Tumor/non-tumor paired analysis showed that 69% of HCC samples contained significantly reduced mtDNA, compared with 49.0% of non-tumor counterparts. In 81.40% of HCC samples, mitochondrial transcription factor A (TFAM) was enriched in tumor cells but not in adjacent non-tumor cells. Neither mtDNA depletion nor TFAM overexpression correlated with the degree of cell differentiation, though TFAM expression correlated with tumor size.