Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees.

Biochemical and molecular genetic evidence is presented that in six independent pedigrees the development of Leber hereditary optic neuropathy (LHON) is due to the same primary mutation in the mitochondrial ND1 gene. A LHON family from the Newcastle area of Great Britain was analyzed in depth to det...

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मुख्य लेखकों: Howell, N, Bindoff, L A, McCullough, D A, Kubacka, I, Poulton, J, Mackey, D, Taylor, L, Turnbull, D M
स्वरूप: लेख
भाषा:English
प्रकाशित: 1991
विषय:
Research Article
ऑनलाइन पहुंच:https://ncbi.nlm.nih.gov/pmc/articles/PMC1683233/
https://ncbi.nlm.nih.gov/pubmed/1928099
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spelling pubmed-16832332006-12-06 Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees. Howell, N Bindoff, L A McCullough, D A Kubacka, I Poulton, J Mackey, D Taylor, L Turnbull, D M Am J Hum Genet Research Article Biochemical and molecular genetic evidence is presented that in six independent pedigrees the development of Leber hereditary optic neuropathy (LHON) is due to the same primary mutation in the mitochondrial ND1 gene. A LHON family from the Newcastle area of Great Britain was analyzed in depth to determine the mitochondrial genetic etiology of their disease. Biochemical assays of mitochondrial electron transport in organelles isolated from the platelet/white-blood-cell fraction have established that the members of this family have a substantial and specific lowering of flux through complex I (NADH-ubiquinone oxidoreductase). To determine the site of the primary mitochondrial gene mutation in this pedigree, all seven mitochondrial complex I genes were sequenced, in their entirety, from two family members. The primary mutation was identified as a homoplasmic transition at nucleotide 3460, which results in the substitution of threonine for alanine at position 52 of the ND1 protein. This residue occurs within a very highly conserved hydrophilic loop, is invariantly alanine or glycine in all ND1 proteins, and is adjacent to an invariant aspartic acid residue. This is only the second instance in which both a biochemical abnormality and a mitochondrial gene mutation have been identified in an LHON pedigree. The sequence analysis of the ND81 gene was extended to a further 11, unrelated LHON pedigrees that had been screened previously and found not to carry the mitochondrial ND4/R340H mutation. The ND1/A52T mutation at nucleotide 3460 was found in five of these 11 pedigrees. In contrast, this sequence change was not found in any of the 47 non-LHON controls. The possible role of secondary complex I mutations in the etiology of LHON is also addressed in these studies. 1991-11 /pmc/articles/PMC1683233/ /pubmed/1928099 Text en
institution US National Library of Medicine
collection PubMed Central
language English
format Article
topic Research Article
spellingShingle Research Article
Howell, N
Bindoff, L A
McCullough, D A
Kubacka, I
Poulton, J
Mackey, D
Taylor, L
Turnbull, D M
Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees.
description Biochemical and molecular genetic evidence is presented that in six independent pedigrees the development of Leber hereditary optic neuropathy (LHON) is due to the same primary mutation in the mitochondrial ND1 gene. A LHON family from the Newcastle area of Great Britain was analyzed in depth to determine the mitochondrial genetic etiology of their disease. Biochemical assays of mitochondrial electron transport in organelles isolated from the platelet/white-blood-cell fraction have established that the members of this family have a substantial and specific lowering of flux through complex I (NADH-ubiquinone oxidoreductase). To determine the site of the primary mitochondrial gene mutation in this pedigree, all seven mitochondrial complex I genes were sequenced, in their entirety, from two family members. The primary mutation was identified as a homoplasmic transition at nucleotide 3460, which results in the substitution of threonine for alanine at position 52 of the ND1 protein. This residue occurs within a very highly conserved hydrophilic loop, is invariantly alanine or glycine in all ND1 proteins, and is adjacent to an invariant aspartic acid residue. This is only the second instance in which both a biochemical abnormality and a mitochondrial gene mutation have been identified in an LHON pedigree. The sequence analysis of the ND81 gene was extended to a further 11, unrelated LHON pedigrees that had been screened previously and found not to carry the mitochondrial ND4/R340H mutation. The ND1/A52T mutation at nucleotide 3460 was found in five of these 11 pedigrees. In contrast, this sequence change was not found in any of the 47 non-LHON controls. The possible role of secondary complex I mutations in the etiology of LHON is also addressed in these studies.
author Howell, N
Bindoff, L A
McCullough, D A
Kubacka, I
Poulton, J
Mackey, D
Taylor, L
Turnbull, D M
author_facet Howell, N
Bindoff, L A
McCullough, D A
Kubacka, I
Poulton, J
Mackey, D
Taylor, L
Turnbull, D M
author_sort Howell, N
title Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees.
title_short Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees.
title_full Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees.
title_fullStr Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees.
title_full_unstemmed Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees.
title_sort leber hereditary optic neuropathy: identification of the same mitochondrial nd1 mutation in six pedigrees.
publishDate 1991
url https://ncbi.nlm.nih.gov/pmc/articles/PMC1683233/
https://ncbi.nlm.nih.gov/pubmed/1928099
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