Investigation of mitochondrial sequence variants associated with aminoglycoside-induced ototoxicity in South African TB patients on aminoglycosides

Human, H.J.; Hagen, Christian Munch; Jong, Greetje de; Harris, Tashneem; Lombard, Debbie; Christiansen, Michael; Bardien, Soraya

doi:10.1016/j.bbrc.2010.02.075

Cited by 26 publications

(28 citation statements)

References 27 publications

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“…5 Genetic predisposition may be predicted by identification of mutations in the MT-RNR1 gene. 5,6 The literature suggests that mitochondrial mutations in the 12S rRNA are rare (0.09% -3.96%), depending on the population studied. 7,8 Owing to the rarity of these mutations, genetic predisposition may be unlikely to contribute significantly to the excessive risk of ototoxicity seen in developing countries.…”

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confidence: 99%

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Aminoglycoside-induced hearing loss in HIV-positive and HIV-negative multidrug-resistant tuberculosis patients

et al. 2012

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confidence: 99%

“…This study was divided into 2 parts of which the first relates to prevalence of the 6 known aminoglycoside-induced deafness mutations in the MT-RNR1 gene in a cohort of MDR-TB patients. 5,6 Although these data have been published, they are cited where referred to in the text for completeness. The second part involves prospective hearing evaluation.…”

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confidence: 99%

Aminoglycoside-induced hearing loss in HIV-positive and HIV-negative multidrug-resistant tuberculosis patients

et al. 2012

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“…The second variation in this patient, an m.10128C4A missense variation, was also described by Human et al 31 for the same African TB patients with aminoglycoside-induced ototoxicity who harboured the m.10114T4C missense variation. This variation was predicted to be benign, 31 but we found it to substitute a highly conserved amino-acid residue (p.Leu24Met) with a possible deleterious impact. Finally, a well-documented pathogenic m.14484T4C variation (p.Met64Val) was identified in one patient.…”

Section: Non-haplogroup-associated Mtdna Variantsmentioning

confidence: 75%

“…It was also recently reported in two L-haplogroup South African TB patients, with aminoglycoside-induced ototoxicity, that it was predicted to be benign. 31 Indeed, the CI for the resultant p.Ala330Val substitution is relatively low at 0.535 and further in silico evaluation for this variation indicates that it is probably benign and tolerated.…”

Section: Non-haplogroup-associated Mtdna Variantsmentioning

confidence: 93%

“…Two variants (m.10114T4C and m.10128C4A) in the MTND3 gene of complex I were observed in a female patient who presented with eye and muscular involvement (no enzyme data could be generated owing to a poor biopsy). The m.10114T4C missense variation was recently reported to be associated with aminoglycoside-induced ototoxicity in two African TB (Tuberculosis) patients 31 and reported to have an impact on the OXPHOS capacity. This variation leads to the substitution of a poorly conserved aminoacid residue, neutral apolar isoleucine, to a neutral polar threonine at position 19 and have been predicted by in silico analyses to be a benign variation.…”

Section: Non-haplogroup-associated Mtdna Variantsmentioning

confidence: 99%

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Characterization of mtDNA variation in a cohort of South African paediatric patients with mitochondrial disease

et al. 2012

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Mitochondrial disease can be attributed to both mitochondrial and nuclear gene mutations. It has a heterogeneous clinical and biochemical profile, which is compounded by the diversity of the genetic background. Disease-based epidemiological information has expanded significantly in recent decades, but little information is known that clarifies the aetiology in African patients. The aim of this study was to investigate mitochondrial DNA variation and pathogenic mutations in the muscle of diagnosed paediatric patients from South Africa. A cohort of 71 South African paediatric patients was included and a high-throughput nucleotide sequencing approach was used to sequence full-length muscle mtDNA. The average coverage of the mtDNA genome was 81 ± 26 per position. After assigning haplogroups, it was determined that although the nature of non-haplogroup-defining variants was similar in African and non-African haplogroup patients, the number of substitutions were significantly higher in African patients. We describe previously reported disease-associated and novel variants in this cohort. We observed a general lack of commonly reported syndrome-associated mutations, which supports clinical observations and confirms general observations in African patients when using single mutation screening strategies based on (predominantly non-African) mtDNA disease-based information. It is finally concluded that this first extensive report on muscle mtDNA sequences in African paediatric patients highlights the need for a full-length mtDNA sequencing strategy, which applies to all populations where specific mutations is not present. This, in addition to nuclear DNA gene mutation and pathogenicity evaluations, will be required to better unravel the aetiology of these disorders in African patients.

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The prevalence of mitochondrial mutations associated with aminoglycoside‐induced sensorineural hearing loss in an NICU population

et al. 2011

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Several mitochondrial DNA variants increase risk for developing sensorineural hearing loss following exposure to aminoglycoside antibiotics, a particular concern in the premature infant population, as many of these babies spend time in neonatal intensive care units and are treated with aminoglycosides. To determine the relative prevalence of five mitochondrial DNA variants in the 12S rRNA gene, MT-RNR1, we genotyped 703 neonatal intensive care unit patients and 1473 individuals from the general Iowa population. We found that the aggregate frequency of these variants (∼1.8%) was comparable between populations. Although no hearing loss was detected by newborn hearing screens in the at-risk patients, these neonatal intensive care unit graduates have an increased life-time risk for developing aminoglycoside-induced deafness.

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Investigation of mitochondrial sequence variants associated with aminoglycoside-induced ototoxicity in South African TB patients on aminoglycosides

Cited by 26 publications

References 27 publications

Aminoglycoside-induced hearing loss in HIV-positive and HIV-negative multidrug-resistant tuberculosis patients

Aminoglycoside-induced hearing loss in HIV-positive and HIV-negative multidrug-resistant tuberculosis patients

Characterization of mtDNA variation in a cohort of South African paediatric patients with mitochondrial disease

The prevalence of mitochondrial mutations associated with aminoglycoside‐induced sensorineural hearing loss in an NICU population

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