Leber’s hereditary optic neuropathy plus dystonia caused by the mitochondrial ND1 gene m.4160 T > C mutation

Analysis of Human Clinical Mutations of Mitochondrial ND1 in a Bacterial Model System for Complex I

“…In two other reports, individuals with ND1_Y277C (A4136G) also carried a different confirmed LHON mutation, ND4_R340H [72,73]. More recently, new insights were obtained [60]. A 19year-old male was identified with both mutations, ND1_Y277C (A4136G) and ND1_L285P (T4160C), but his mother and sister carried only the ND1_Y277C (A4136G) mutation.…”

Mitochondrial complex I subunit MT-ND1 mutations affect disease progression

“…It is mainly involved in the assembly of respiratory chain complex I, the ubiquinone binding domain and proton pump structure of complex I, and affects oxidative phosphorylation in the electron transport chain [ 17 ]. Mutations in the MT-ND1 causing defects in the MT-ND1 protein can affect normal physiological activities [ [18] , [19] , [20] ], and mutations in different regions of MT-ND1 can cause varying degrees of enzyme damage [ 20 ].…”

“…If a mutation in MT-ND1 leads to a decrease in normal MT-ND1 levels, the inability of complex I to assemble properly will also lead to the degradation of other subunits. A deficiency of MT-ND1 and a decrease in steady-state levels of other nuclear encoded subunits were observed in the m.3571dupC mutant cell line [ 21 ]; a decrease in the steady-state level of the NDUFB8 subunit was observed in cells with a m.3946G > A/ND1 mutation [ 26 ]; and the m.4160T > C/ND1 mutation not only damages the MT-ND1 protein, but also might affect the stability of MT-ND4, MT-ND5, and the nuclear DNA-encoded subunits NDUFB8 and succinate dehydrogenase complex iron sulfur subunit B (SDHB) [ 19 ]. Thus, a lack of MT-ND1 can affect the assembly of respiratory chain complex I and inhibit the assembly of complete enzymes.…”

“…The accumulation of autophagic substrates will poison cells [ 37 ], representing another possible mechanism of LHON. The rare occurrence of m.4160T > C/MT-ND1 can lead to a decrease in MT-ND1 levels and the CI oxygen consumption rate (OCR), which is a pathogenic mutation of LHON [ 19 ]. Therefore, MT-ND1 mutation is one of the important pathogenic factors of LHON.…”

“…Therefore, studying the pathogenic thresholds of different MT-ND1 mutations will contribute to the accurate diagnosis of diseases. In addition, the mutation levels of MT-ND1 in different tissues of gene mutation carriers might vary, for example the MT-ND1 mutation load could be different in different tissue samples such as blood, skeletal muscle, urine, and in different cell types [ 19 , 75 , 77 ]. This means that mutation level detection in a single tissue sample might make it difficult to predict the occurrence and development of the disease.…”