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Case Reports
. 2003 Jun;72(6):1571-7.
doi: 10.1086/375654. Epub 2003 May 6.

Multiple Mutations of MYO1A, a Cochlear-Expressed Gene, in Sensorineural Hearing Loss

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Multiple Mutations of MYO1A, a Cochlear-Expressed Gene, in Sensorineural Hearing Loss

Francesca Donaudy et al. Am J Hum Genet. .
Free PMC article

Abstract

Myosin I isozymes have been implicated in various motile processes, including organelle translocation, ion-channel gating, and cytoskeleton reorganization. Unconventional myosins were among the first family of proteins found to be associated with hearing loss in both humans and mice. Here, we report the identification of a nonsense mutation, of a trinucleotide insertion leading to an addition of an amino acid, and of six missense mutations in MYO1A cDNA sequence in a group of hearing-impaired patients from Italy. MYO1A, which is located within the DFNA48 locus, is the first myosin I family member found to be involved in causing deafness and may be a major contributor to autosomal dominant-hearing loss.

Figures

Figure  1
Figure 1
Nonsense and frameshift mutations. A, Sequence data of the nonsense R93X mutation. B, Results showing the presence of R93X after AvaII restriction enzyme digestion. The presence of the mutation destroys a restriction site. ND = not digested; M = mutated; N = normal. C, Electrophoretic results showing the presence of the 349-350insCTT mutation. Fluorescent primers were designed and used for detecting the presence of the insertion in a 3100 ABI Prism Capillary Electrophoresis.
Figure  2
Figure 2
Ribbon representation of a 3D model of the MYO1A motor domain. The model was obtained using the experimentally determined structure of Dictyostelium discoideum myosin-IE as a template (Kollmar et al. 2002). The two motor domains share 45% sequence identity with each other. The homology-model building was carried out using a pairwise alignment of these two proteins and the Nest facility of the Jackal protein structure modeling package. The degree of conservation of the residues in MYO1A was analyzed using ConSurf (Glaser et al. 2003); residue conservation scores, calculated using 42 homologous sequences, are color coded onto the structure of MYO1A (see key). ConSurf assigns amino acid conservation grades in range 1–9, where 9 is maximal conservation and 1 is minimal conservation—that is, highly variable. The residues mutated in the MYO1A motor domain are shown using ball-and-stick representation (insets).
Figure  3
Figure 3
Myo1a and Myo6 in mouse inner ear. At each of E14, E16, E18, and P0, one RNA preparation was used to amplify the two genes by RT-PCR. Amplifications were carried out with (+) and without (−) reverse transcriptase, by use of inner-ear RNA, genomic DNA (G), and H20 control (H). The Myo1a fragment of 417 bp is the predicted size of the amplicons spanning Myo1a exons 13–16. Predictions were verified by sequencing the products. The Myo6 amplification (Ahituv et al. 2000) was used as a positive control for inner-ear expression. Fragment of 385 bp and 880 bp represents the predicted sizes of these amplicons from cDNA and genomic DNA, respectively.

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