Audiologic and genetic features of the A3243G mtDNA mutation

Abstract

Background: Mitochondrial mutations have been shown to be responsible for syndromic and nonsyndromic hearing impairment.

Aim: To assess the genotypic-phenotypic correlation of mitochondrial DNA mutations in three generations of a single family.

Methods: A single family with maternally inherited diabetes and hearing loss was recruited. Genomic DNA was subject to polymerase chain reaction-restriction fragment length polymorphism analysis (ApaI) for A3243G mutation detection and confirmation with direct DNA sequencing. The degree of heteroplasmy for the A3243G mutation in blood DNA samples was quantified. In addition, we reviewed audiological data of A3243G-associated hearing loss cases from the literature to provide details of audiologic features.

Results: Six of 11 family members were recruited. All affected members harbored the A3243G mutation. Four of six members had diabetes. Five of five affected members demonstrated hearing loss ranging from mild to severe. The degree of heteroplasmy ranged from 5.51% to 27.74%.

Conclusions: Patients with a greater percentage of heteroplasmy have a trend toward more severe phenotypic presentations. Hearing loss is bilateral, sensorineural, and symmetric. The main audiogram shapes found were sloping. Additional studies are necessary to clarify the relationship between degree of heteroplasmy and phenotypic presentation.

FIG. 1.

Three-generation pedigree of a single family affected with the A3243G mitochondrial DNA (mtDNA) mutation. The affected individuals are represented by filled symbols. The proband (386201) is indicated by an arrow. No data were available for individual 386–203.

FIG. 2.

Identification of the A3243G mutation in mtDNA using the ApaI restriction enzyme analysis of polymerase chain reaction (PCR) products. The primer pair generates a PCR product of 161 bp. PCR products amplified from mutant A3243G allele(s) are digested into 87 and 74 bp, whereas normal control DNA products are not digested. Lane 1 for normal control DNA; lanes 2 and 8 for DNAs for individuals without A3243G mutations; lanes 3–7 for individuals with A3243G mutations; lane 9 for 100 bp DNA ladder; lane 10 for negative control; lane 3: 386202; lane 4: 386201; lane 5: 386105; lane 6: 386104; lane 7: 386102; lane 8: 386101.

FIG. 3.

Pure-tone audiometry demonstrating mild to severe hearing loss of five individuals with the A3243G mtDNA mutation.