Dataset Information

Analysis of the heteroplasmy level and transmitted features in hearing-loss pedigrees with mitochondrial 12S rRNA A1555G mutation.

ABSTRACT: Mitochondrial cytopathies are characterized by a large variability of clinical phenotypes and severity. The amount of mutant mitochondrial DNA (mtDNA) in a cell, called the heteroplasmy level, is an important determinant of the degree of mitochondrial dysfunction and therefore disease severity. Understanding the distribution of heteroplasmy levels across a group of offspring is an important step in understanding the inheritance of diseases. Recently, the mtDNA A1555G mutation was found to be associated with non-syndromic and drug-induced hearing loss.Here, we report five pedigrees with multiple members having the A1555G mutation and showing diverse clinical manifestations and different heteroplasmy levels. Clinical evaluations revealed that the hearing impairment phenotypes varied with respect to the severity of hearing loss, age of onset of hearing loss, and pattern of audiometric configuration. These five Chinese pedigrees had different penetrance of hearing loss, ranging from 10-52%. A molecular study showed that the average heteroplasmy rates of the five pedigrees were 31.98% (0-91.35%), 78.28% (32.8-96.08%), 87.99% (82.32-94.65%), 93.34% (91.02-95.05%), and 93.57% (91.38-94.24%). There was no gradual tendency of heteroplasmy to increase or decrease along with transmission. A study of the relationship between clinical features and genetic background found that the percentage of deafness was 0 when the heteroplasmy level was less than 50%, 25% when the heteroplasmy level was 50-80%, 47.06% when the heteroplasmy level was 80-90%, and 57.58% when the heteroplasmy level exceeded 90%. The risk of deafness rose with the heteroplasmy level.The results suggest that there are large random shifts in the heteroplasmy level between mothers and offspring with the A1555G mutation; heteroplasmy could disappear randomly when the heteroplasmy level of the pedigree was low enough, and no regular pattern was found. The heteroplasmy level may be one of the factors influencing the penetrance of deafness caused by the mtDNA A1555G mutation.

SUBMITTER: Zhu Y

PROVIDER: S-EPMC3933286 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Analysis of the heteroplasmy level and transmitted features in hearing-loss pedigrees with mitochondrial 12S rRNA A1555G mutation.

Zhu Yuhua Y Huang Shasha S Kang Dongyang D Han Mingyu M Wang Guojian G Yuan Yongyi Y Su Yu Y Yuan Huijun H Zhai Suoqiang S Dai Pu P

BMC genetics 20140217

<h4>Background</h4>Mitochondrial cytopathies are characterized by a large variability of clinical phenotypes and severity. The amount of mutant mitochondrial DNA (mtDNA) in a cell, called the heteroplasmy level, is an important determinant of the degree of mitochondrial dysfunction and therefore disease severity. Understanding the distribution of heteroplasmy levels across a group of offspring is an important step in understanding the inheritance of diseases. Recently, the mtDNA A1555G mutation ...[more]

PMID: 24533451

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Project description:Recent studies suggest that certain mitochondrial haplogroup markers and some specific variants in mitochondrial haplogroup may also influence the phenotypic expression of particular mitochondrial disorders. In this report, the clinical, genetic, and molecular characterization were identified in a Chinese pedigree with the aminoglycoside antibiotic (AmAn)-induced deafness and nonsyndromic hearing loss (NSHL). The pathogenic gene responsible for this hereditary NSHL pedigree was determined by Microarray chip, which possessed the nine NSHL hot-spot mutations, including GJB2 (35delG, 176dell6bp, 235de1C, and 299delAT), GJB3 (538C>T), SLC26A4 (IVS7-2A>G and 2168A>G), and mitochondrial DNA (mtDNA) 12S rRNA (C1494T and A1555G). Only the homoplasmic A1555G mutation was detected, which was confirmed by direct sequencing. Also, real-time amplification refractory mutation system quantitative polymerase chain reaction methodology was performed to calculate the A1555G mutation load. The proband's complete mtDNA genome were amplified and direct sequencing was performed to determine the mitochondrial haplogroup and private mutations. The proband's mitochondrial haplogroup belonges to M7b1 and a private mutation MTCOX2 G7598A (p.Ala 5 Thr) is found. Phylogenetic analysis of COX2 polypeptide sequences demonstrates that the alanine residue is relatively conserved, but owing to the missense mutation (p.Ala 5 Thr), its side chain hydrophobicity will be changed, and what is more, as it is adjacent to a glutamine residue, which is highly conserved and hydrophilic, in an evolutionary stable domain; G7598A (p.Ala 5 Thr) may alter the protein secondary structure and physiological function of COX2 and, thus, aggravate the mitochondrial dysfunction conferred by the A1555G mutation. Furthermore, the G7598A mutation is absent in 100 unrelated healthy controls; therefore, G7598A (p.Ala 5 Thr) in the mitochondrial haplogoup M7b1 may have a modifying role, enhancing its penetrance and severity, in the AmAn-induced deafness and NSHL associated with 12S rRNA A1555G mutation in the Han Chinese pedigree.

Dataset Information

Analysis of the heteroplasmy level and transmitted features in hearing-loss pedigrees with mitochondrial 12S rRNA A1555G mutation.

Publications

Analysis of the heteroplasmy level and transmitted features in hearing-loss pedigrees with mitochondrial 12S rRNA A1555G mutation.

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