title: Mitochondrial COX2 G7598A mutation may have a modifying role in the phenotypic manifestation of aminoglycoside antibiotic-induced deafness associated with 12S rRNA A1555G mutation in a Han Chinese pedigree.
abstract: 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.
authors.affiliation: First Clinical College, Fujian Medical University, Fuzhou, China.
authors.forename: Tianbin
authors.initials: T
authors.lastname: Chen
authors.forename: Qicai
authors.initials: Q
authors.lastname: Liu
authors.forename: Ling
authors.initials: L
authors.lastname: Jiang
authors.forename: Can
authors.initials: C
authors.lastname: Liu
authors.forename: Qishui
authors.initials: Q
authors.lastname: Ou
mesh_terms: D000617:Aminoglycosides / Q000009:adverse effects*; D000900:Anti-Bacterial Agents / Q000009:adverse effects; D044466:Asian People / Q000208:ethnology / Q000235:genetics; D002675:Child, Preschool; D000072259:Connexin 26; D017630:Connexins; D051546:Cyclooxygenase 2 / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D034381:Hearing Loss / Q000139:chemically induced / Q000208:ethnology / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D010641:Phenotype; D012335:RNA, Ribosomal / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D017630:Connexins; D004272:DNA, Mitochondrial; C000607042:GJB2 protein, human; D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S; D000072259:Connexin 26; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human