University of Oulu

Mitochondrial DNA sequence variation in patients with sensorineural hearing impairment and in the Finnish population

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Author: Lehtonen, Mervi1,2,3
Organizations: 1University of Oulu, Faculty of Medicine, Department of Neurology
2University of Oulu, Faculty of Medicine, Department of Medical Biochemistry and Molecular Biology
3University of Oulu, Biocenter Oulu
Format: ebook
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.7 MB)
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Language: English
Published: 2002
Publish Date: 2002-11-08
Thesis type: Doctoral Dissertation
Defence Note: Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in the Auditorium 8 of the University Hospital of Oulu, on November 8th, 2002, at 12 noon.
Reviewer: Docent Kirsi Huoponen
Professor Ilmari Pyykkö


Sensorineural hearing impairment (SNHI) is a well-recognized manifestation of mitochondrial diseases and occurs either in a non-syndromic form or as a part of a syndrome. Mitochondrial deafness is bilateral, usually progressive and is inherited maternally. Approximately 70% of patients with the most common syndromes, Kearns-Sayre, MELAS or MERRF, have SNHI. Several mutations in mitochondrial DNA (mtDNA) have been found to cause non-syndromic SNHI, including 1555A>G, 7445T>C, 7472insC and 7511T>C.

In order to estimate prevalences of pathogenic mtDNA mutations in population-based cohorts of patients with SNHI, we obtained samples from 133 patients with SNHI, reportedly representing 117 separate maternal lineages. We found five patients with the 3243A>G mutation and three with the 1555A>G mutation, whereas the other point mutations associated with SNHI were absent. The frequencies of the mutations in the cohort were thus 4.3 % for 3243A>G and 2.6 % for 1555A>G, suggesting a total frequency of 6.9 % for mtDNA mutations known to be associated with hearing impairment.

We found a mutation 10044A>G, which has been reported as pathogenic, in our patients with SNHI, but we also found it among the controls. Our results show it to be a homoplasmic polymorphism associated with a fairly rare haplotype within mtDNA haplogroup H which has recently been confirmed as subcluster H4. These results highlight the difficulty in determining the pathogenicity of a mtDNA mutation when it is identified only in one family. Therefore, in addition to the previously published criteria, we suggest that a sufficient number of haplotype-specific controls should be screened before the pathogenic nature of a mtDNA mutation can be verified.

We determined the complete mtDNA sequences for 121 Finns, and after complementing our recent data, for a total of 192 Finns, and were able to construct a phylogenetic network based on complete mtDNA sequences, the largest set of complete sequences available at that time. These mtDNAs provide a rich source of information for studies in population genetics and a potential tool for analysing new substitutions and genotypes that entail a risk of mitochondrial disease.

We used the phylogenetic network to find new pathogenic mutations or risk genotypes for SNHI. The entire coding region sequences of mtDNA were determined in 32 patients with SNHI and compared with the network. The patients were found to harbour more rare polymorphisms and haplotypes than the controls and to show increased variation in their mtDNA sequences, suggesting mildly deleterious effects for these substitutions. Two of the new mutations were suggested as putatively pathogenic.

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Series: Acta Universitatis Ouluensis. D, Medica
ISSN-E: 1796-2234
ISBN: 951-42-6849-0
ISBN Print: 951-42-6848-2
Issue: 700
Copyright information: © University of Oulu, 2002. This publication is copyrighted. You may download, display and print it for your own personal use. Commercial use is prohibited.