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. 2002 May 28;99(11):7518-23.
doi: 10.1073/pnas.102091699.

From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30

Tom Walsh  1 , Vanessa Walsh, Sarah Vreugde, Ronna Hertzano, Hashem Shahin, Smadar Haika, Ming K Lee, Moien Kanaan, Mary-Claire King, Karen B Avraham
Affiliations

From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30

Tom Walsh et al. Proc Natl Acad Sci U S A. .

Abstract

Normal vision in Drosophila requires NINAC, a class III myosin. Class III myosins are hybrid motor-signaling molecules, with an N-terminal kinase domain, highly conserved head and neck domains, and a class III-specific tail domain. In Drosophila rhabdomeres, NINAC interacts with actin filaments and with a PDZ scaffolding protein to organize the phototransduction machinery into a signaling complex. Recessive null mutations in Drosophila NINAC delay termination of the photoreceptor response and lead to progressive retinal degeneration. Here, we show that normal hearing in humans requires myosin IIIA, the human homolog of NINAC. In an extended Israeli family, nonsyndromic progressive hearing loss is caused by three different recessive, loss-of-function mutations in myosin IIIA. Of 18 affected relatives in Family N, 7 are homozygous and 11 are compound heterozygous for pairs of mutant alleles. Expression of mammalian myosin IIIA is highly restricted, with the strongest expression in retina and cochlea. The involvement of homologous class III myosins in both Drosophila vision and human hearing is an evolutionary link between these sensory systems.

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Figures

Figure 1
Figure 1
Progressive hearing loss in Family N. Hearing thresholds in decibels (dB), measured by pure-tone audiometry, are shown for sound frequencies ranging from very low (250 Hz) to very high (8000 Hz). Hearing thresholds (with standard errors) are shown for affected relatives of Family N. The number of audiograms (N) included for relatives aged 25–39, 40–49, 50–59, and 60+ years are indicated.
Figure 2
Figure 2
Chromosome 10p haplotypes linked to deafness in Family N. Deaf individuals are indicated by black symbols. All individuals included in the pedigree are more than 30 years of age, older than onset of hearing loss in the family. Under a recessive model with age-dependent expression, a 13-cM region of chromosome 10p12-p11 bounded by D10S1749 and D10S1654 is linked to hearing loss. Deaf individuals are homozygous or compound heterozygous for any of five different extended haplotypes, indicated in orange, green, pink, yellow, and blue. Homozygosity mapping did not reveal any regions of homozygosity shared by all deaf individuals, suggesting multiple mutant alleles leading to deafness in the family.
Figure 3
Figure 3
Three different mutations of myosin IIIA are associated with deafness in Family N. (a) 3126 T->G in exon 28 changes TAT to TAG and hence creates a stop at codon 1043. This mutation is illustrated by genomic DNA sequences of unaffected heterozygote III:8 and affected homozygote III:6. All haplotypes shown in green, orange, and pink in Fig. 2 carry this nonsense mutation. (b) 1777(-12) G->A in intron 17 causes a splicing error that leads to deletion of exon 18 and a stop at codon 668. This mutation is illustrated by genomic sequence of unaffected heterozygote II:9. The consequence of this mutation is illustrated by cDNA sequences of compound heterozygote III:14 compared with a wild-type control. Furthermore, amplification of exons 16–19 from cDNA of III:14 yields a 183-bp fragment, as expected if exon 18 is deleted from the message. All haplotypes shown in blue in Fig. 2 carry this mutation. (c) 732(-2) A->G in intron 7 destroys the canonical (AG) splice acceptor of exon 8 and seems to lead to an unstable message. This mutation is illustrated by genomic sequence of unaffected heterozygote IV:6 and affected homozygote II:10. The absence of stable message made from this allele is illustrated by comparing SNP genotypes in genomic DNA vs. cDNA of a heterozygous carrier of the mutation, IV:6. The mutation at 732(-2) A->G is in disequilibrium with allele G of the SNP at myosin IIIA bp 2496. Genomic DNA of IV:6 is heterozygous for 2496 G/T, whereas cDNA of IV:6 is hemizygous for 2496 T. Similarly, amplification of exons 16–19 from cDNA of III:14 (b, above) yields the 183-bp message associated with the 1777(-12) G->A allele but not the 310-bp transcript that would be associated with the 732(-2) A->G allele. All haplotypes shown in yellow in Fig. 2 carry the 732(-2) G->A mutation. (d) Sketch of the functional domains of myosin IIIA with sites of the Family N mutations indicated.
Figure 4
Figure 4
Expression of Myo3a, Inad, and Myo6 in mouse cochlea. At each of P0, P5, and P10, one RNA preparation was used to amplify the three genes by RT-PCR. Amplifications were carried out with (+) and without (−) reverse transcriptase, by using cochlear RNA, genomic DNA (G), and water control (W). Myo3a fragments of 521 bp and 379 bp are the predicted sizes of the amplicons spanning Myo3a exons 30–35 and the same amplicon with exon 34 deleted in-frame. Predictions were verified by sequencing the products. The InaD fragment of 179 bp and the Myo6 fragment of 385 bp represent the predicted sizes of these amplicons from cDNA.
Figure 5
Figure 5
Expression of myosin IIIA in mouse cochlear hair cells demonstrated by in situ hybridization. (A) Whole mount of mouse cochlea at P0 reveals specific labeling of hair cells by the Myo3a antisense probe (arrows). The line indicates the orientation of the cross sections. (B) Cross section of the cochlear duct showing specific labeling of the inner hair cells (IHC) and outer hair cells (OHC) with Myo3a antisense probe. (C) Cross section of the cochlear duct showing absence of labeling with the Myo3a sense probe.
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