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Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent occurrences of the common mutations

Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates... The mitochondrial DNAs (mtDNA) from 17 Caucasian 11778‐positive and 30 Caucasian 11778‐negative Leber's hereditary optic neuropathy (LHON) patients were PCR‐amplified and subjected to high resolution restriction endonuclease analysis. Concurrently, all patient mtDNAs were screened for the common primary LHON mtDNA mutations at nucleotide pairs (nps) 3460, 11778, and 14484, the ambiguous intermediate‐risk LHON mtDNA mutations at nps 5244 and 15257, and the secondary LHON mtDNA mutations at nps 3394, 4216, 4917, 7444, 13708, and 15812. Phylogenetic analysis was performed using mtDNA haplotype data from the 47 LHON patients and 175 non‐LHON Caucasian controls. The superimposition of the LHON mutation screening results upon the Caucasian mtDNA phylogeny revealed (1) 35 different LHON haplotypes, (2) that all three common primary mutations have occurred multiple times in Caucasians, (3) that while recurrent mutation is common for the primary mutations, secondary mutations tend to be lineage‐specific, (4) that the np 15257 mutation was confined to a single mtDNA lineage but may be etiologically important in some LHON cases since it was found in a LHON pedigree which lacked a common primary mutation; complete sequence analysis of the proband mtDNA revealed only a single other candidate missense mutation (at np 10663 of the ND4L gene) of uncertain pathological significance; and (5) that the np 14484 mutation may be less pathogenic than either the np 3460 or np 11778 mutations, as this mutation most commonly occurred on a single mtDNA lineage and almost always in association with secondary LHON mutations. A phylogenetic ageneous disease has thus provided key genetic data bearing on the relative pathogenicity of the LHON‐associated mtDNA mutations. © 1995 Wiley‐Liss, Inc. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Human Mutation Wiley

Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent occurrences of the common mutations

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References (57)

Publisher
Wiley
Copyright
Copyright © 1995 Wiley Subscription Services, Inc., A Wiley Company
ISSN
1059-7794
eISSN
1098-1004
DOI
10.1002/humu.1380060405
pmid
8680405
Publisher site
See Article on Publisher Site

Abstract

The mitochondrial DNAs (mtDNA) from 17 Caucasian 11778‐positive and 30 Caucasian 11778‐negative Leber's hereditary optic neuropathy (LHON) patients were PCR‐amplified and subjected to high resolution restriction endonuclease analysis. Concurrently, all patient mtDNAs were screened for the common primary LHON mtDNA mutations at nucleotide pairs (nps) 3460, 11778, and 14484, the ambiguous intermediate‐risk LHON mtDNA mutations at nps 5244 and 15257, and the secondary LHON mtDNA mutations at nps 3394, 4216, 4917, 7444, 13708, and 15812. Phylogenetic analysis was performed using mtDNA haplotype data from the 47 LHON patients and 175 non‐LHON Caucasian controls. The superimposition of the LHON mutation screening results upon the Caucasian mtDNA phylogeny revealed (1) 35 different LHON haplotypes, (2) that all three common primary mutations have occurred multiple times in Caucasians, (3) that while recurrent mutation is common for the primary mutations, secondary mutations tend to be lineage‐specific, (4) that the np 15257 mutation was confined to a single mtDNA lineage but may be etiologically important in some LHON cases since it was found in a LHON pedigree which lacked a common primary mutation; complete sequence analysis of the proband mtDNA revealed only a single other candidate missense mutation (at np 10663 of the ND4L gene) of uncertain pathological significance; and (5) that the np 14484 mutation may be less pathogenic than either the np 3460 or np 11778 mutations, as this mutation most commonly occurred on a single mtDNA lineage and almost always in association with secondary LHON mutations. A phylogenetic ageneous disease has thus provided key genetic data bearing on the relative pathogenicity of the LHON‐associated mtDNA mutations. © 1995 Wiley‐Liss, Inc.

Journal

Human MutationWiley

Published: Jan 1, 1995

Keywords: Leber's hereditary optic neuropathy; Mitochondrial DNA mutations; Mitochondrial DNA haplotypes; Phylogenetic analysis; Primary LHON mutations

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