Учебники / Genetic Hearing Loss Willems 2004

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members of both families share a similar phenotype of postlingual, progressive, sensorineural hearing loss. All a ected individuals have normal speech and language development.

II.AUDIOMETRIC ANALYSIS OF DFNA10 PHENOTYPE

A.Evolution of DFNA10 Phenotype with Age

1.Methods

Pure tone and speech audiograms were obtained on 27 a ected individuals in Family A, age range 15–87 years. Air conduction thresholds (decibels hearing level) were used for cross-sectional linear regression analysis, to analyze progression at each frequency. Bone conduction levels were obtained to confirm sensorineural hearing loss. To explore the e ects of presbyacusis on the DFNA10 phenotype, analyses were repeated with thresholds corrected for age and sex according to ISO 7029 norms.

2.Results

All a ected individuals dated the onset of hearing loss within the first three decades of life (5). During the second and third decades of life, fairly rapid progression of hearing loss is seen (Fig. 2). The derived mean threshold deterioration is approximately 2–3 decibels (dB) per year over all frequencies. After age 30 years, the rate of progression of hearing loss slows to approximately 0.6 dB/year, which, when corrected for the e ects of presbyacusis, is not significant. Thus, DFNA10 hearing loss is postlingual in onset, progressive over the first three decades of life, and followed by further gradual progression that can be attributed to normal presbyacusis.

B.Phenotype Comparison of Families A and B

Linear regression analysis was performed using pure tone thresholds obtained from 25 a ected persons from Family A and 17 a ected persons from Family B. Age-related audiograms were constructed (Fig. 3). Both families demonstrate flat-to-gently sloping audiograms, which evolve with advancing age to a steeply sloping configuration. The hearing loss in Family A appears to be slightly more severe than in Family B.

III.CLONING OF EYA4, THE CAUSATIVE GENE OF DFNA10

A.Linkage Mapping

The DFNA10 locus was originally mapped by linkage analysis on the American Family A in 1996 to a 15-cM interval on chromosome 6q22–23

Figure 2 Cross-sectional threshold-on-age data (air conduction threshold in right ear). Circles and bold solid lines relate to the linear regression analysis in all cases (age over 15 years). Asterisks and dotted lines relate to age-corrected thresholds. Audiograms from a single individual from Family A are shown separately with squares and thin solid lines. (From Ref. 5.)

Figure 3 Age-related typical audiograms of (A) Family A and (B) Family B. Italics indicate age in years. (From Ref. 5.)

Figure 5 Sequencing results for EYA4. (A) In Family A, a portion of the electropherogram for EYA4 exon 12 sequenced from subcloned PCR products demonstrates the insertion of 2 adenine residues (arrows) in one allele of the a ected individual; wild-type sequence is seen in the other allele (compare to una ected alleles). (B) In Family B, a portion of the electropherogram for EYA4 exon 20 shows a cytosine- to-thymine transition (arrow), resulting in a premature stop codon (TGA). (From Ref. 3.)

(Fig. 4). Direct sequencing of exon 12 produced an electropherogram featuring the superimposition of two sequences, suggesting a frameshift mutation. By sequencing of subclones of exon 12 PCR products from a ected and un- a ected family members, the mutation was characterized as the insertion of two adenine residues at position 1468 (1468insAA) (Fig. 5A). This mutation is predicted to generate a frameshift and premature stop codon in exon 14.

2.Mutation Screening of Family B

SSCP analysis of EYA4 in Family B revealed no band shifts segregating with the hearing loss; however, direct sequencing of all exons identified a cy- tosine-to-thymine transition in exon 20 at position 2200 (2200C!T) that segregated with the hearing loss. This base change converts an arginine codon (CGA) to a stop codon (TGA) (Fig. 5B).

IV. EYA PROTEIN STRUCTURE AND FUNCTION

A.General Structure of EYA Proteins

The EYA gene family encodes a family of transcriptional activators that interact with other proteins in a conserved regulatory hierarchy to ensure