The spectrum of mitochondrial DNA mutations in families with Leber hereditary optic neuroretinopathy

Abstract

The mitochondrial complex I genes were sequenced in seven Leber hereditary optic neuroretinopathy (LHON) families without the ND4/11,778 and ND1/3460 mutations. Four replacement mutations restricted only to LHON families were found, one in the ND1 gene at nt 4025, and three in the ND5 gene at nt 12,811, 13,637, and 13,967. The mutations did not change evolutionarily conserved amino acids suggesting that they are not primary LHON mutations in these families. They may be considered as secondary LHON mutations serving as exacerbating factors in an appropriate genetic background. A complex III mutation, cyt b/15,257, has been suggested to be one of the primary mutations causing LHON. Its presence was determined for 23 Finnish LHON families, and it was detected in two families harboring the ND4/11,778 mutation. Similarly, complex IV mutation COI/7444 was screened in Finnish LHON families, and it was found in one family carrying the ND1/3460 mutation.

Molecular genetic basis of primary inherited optic neuropathies

“…Secondary pathogenic mutations include np G13708A, G15812A, A4917G, T4216C, G9804A, G9438A, and G15257A. [16][17][18] The role of the European haplotype J (G15812A, G15257A, G13708A, and T4216C) in disease expression is still unclear. 19 In particular, approximately 75% of patients with the 14484 mutation have this haplotype, while it is only found in B10% of mtDNAs from the general European population.…”

Functional alterations of the mitochondrially encoded ND4 subunit associated with Leber's hereditary optic neuropathy

“…To date, several point mutations in mitochondrial DNA (mtDNA) have been associated with LHON [1][2][3]. The most frequent of these mutations [1][2][3] is the substitution at nucleotide position (np) 11,778 in the ND4 subunit of complex I [4--6].…”

“…Hence, less free energy is available to be converted into proton pumping and ultimately into ATP synthesis during the oxidation of NADH by the LHON-mutated complex I. The decrease in energetic efficiency of this altered complex I, although partial, may become critical with ageing and/or in relation to other aetiological factors (see [1][2][3][4][5][6][7][8][9][10] for discussion of these factors).…”

“…To date, several point mutations in mitochondrial DNA (mtDNA) have been associated with LHON [1][2][3]. The most frequent of these mutations [1][2][3] is the substitution at nucleotide position (np) 11,778 in the ND4 subunit of complex I [4--6]. The functional defect that arises from the amino acid substitution (Arg34°---~His [4]) caused by this mutation is not clear yet [4,[6][7][8], even if a recent report has shown a 25% decrease in complex I activity measured with a short analogue of ubiquinone [9].…”

Mitochondrial medicine – recent advances

“…Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease causing blindness predominantly in young men [34], and three different point mutations of mtDNA genes encoding complex I subunits are found in more than 90% of cases [8,35]37].…”