title: Investigation of mitochondrial sequence variants associated with aminoglycoside-induced ototoxicity in South African TB patients on aminoglycosides.
abstract: A known side effect of aminoglycoside antibiotics is the development of permanent hearing loss. As South Africa is currently facing a tuberculosis (TB) epidemic, with an increasing number of multi-drug resistant tuberculosis (MDR-TB) infections, the use of aminoglycosides is on the increase. It is therefore important to determine whether the mitochondrial mutations associated with aminoglycoside-induced hearing loss occur at high frequencies in particular ethnic groups in our population. A total of 115 mainly MDR-TB patients all on aminoglycosides and 439 controls representative of the main ethnic groups in South Africa were screened for six mutations using the SNaPshot technique. Furthermore, the mitochondrial genomes of eight patients with ototoxicity were sequenced. Homoplasmic mutations were found in controls (A1555G in 0.9% of Black controls and A827G in 1.1% of Afrikaner controls) which reveal that a significant proportion of the South African population is genetically predisposed to developing aminoglycoside-induced hearing loss. The 961 delT+insC((n)) and T961G variants were found at frequencies of >1% indicating that both are probably non-pathogenic polymorphisms. Sequencing of the entire mitochondrial genome in eight patients did not reveal any mutations in the MT-RNR1 gene. However, two potentially pathogenic variants, T10114C (I19T in MT-ND3) and T15312C (I189T in MT-CYB) were found that may impact on the oxidative phosphorylation capacity and warrant further investigation for their possible role in this disorder. It is imperative that the genetic basis of this potentially preventable condition be investigated, particularly in countries where aminoglycosides are still commonly used, in order to identify individuals and/or ethnic groups who are at risk for this type of hearing loss.
authors.affiliation: Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa.
authors.forename: Hanniqué
authors.initials: H
authors.lastname: Human
authors.forename: Christian M
authors.initials: CM
authors.lastname: Hagen
authors.forename: Greetje
authors.initials: G
authors.lastname: de Jong
authors.forename: Tashneem
authors.initials: T
authors.lastname: Harris
authors.forename: Debbie
authors.initials: D
authors.lastname: Lombard
authors.forename: Michael
authors.initials: M
authors.lastname: Christiansen
authors.forename: Soraya
authors.initials: S
authors.lastname: Bardien
mesh_terms: D000617:Aminoglycosides / Q000009:adverse effects*; D000904:Antibiotics, Antitubercular / Q000009:adverse effects*; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D050259:Genes, Mitochondrial; D005820:Genetic Testing / Q000379:methods; D034381:Hearing Loss / Q000139:chemically induced* / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D013019:South Africa; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*
chemical_list: D000617:Aminoglycosides; D000904:Antibiotics, Antitubercular