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. 2000 Nov;67(5):1121-8.
doi: 10.1016/S0002-9297(07)62942-5. Epub 2000 Oct 9.

Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9

A K Lalwani  1 , J A Goldstein, M J Kelley, W Luxford, C M Castelein, A N Mhatre
Affiliations

Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9

A K Lalwani et al. Am J Hum Genet. 2000 Nov.

Abstract

The authors had previously mapped a new locus-DFNA17, for nonsyndromic hereditary hearing impairment-to chromosome 22q12.2-q13. 3. DFNA17 spans a 17- to 23-cM region, and MYH9, a nonmuscle-myosin heavy-chain gene, is located within the linked region. Because of the importance of myosins in hearing, MYH9 was tested as a candidate gene for DFNA17. Expression of MYH9 in the rat cochlea was confirmed using reverse transcriptase-PCR and immunohistochemistry. MYH9 was immunolocalized in the organ of Corti, the subcentral region of the spiral ligament, and the Reissner membrane. Sequence analysis of MYH9 in a family with DFNA17 identified, at nucleotide 2114, a G-->A transposition that cosegregated with the inherited autosomal dominant hearing impairment. This missense mutation changes codon 705 from an invariant arginine (R) to histidine (H), R705H, within a highly conserved SH1 linker region. Previous studies have shown that modification of amino acid residues within the SH1 helix causes dysfunction of the ATPase activity of the motor domain in myosin II. Both the precise role of MYH9 in the cochlea and the mechanism by which the R705H mutation leads to the DFNA17 phenotype (progressive hearing impairment and cochleosaccular degeneration) remain to be elucidated.

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Figures

Figure 1
Figure 1
RT-PCR analysis of MYH9 expression in rat cochlear cDNA. cDNA from several tissues, including the cochlea, was assayed for MYH9 expression via PCR using MYH9-specific primers. A, cDNA from the cochlea, kidney, and lung. All samples yielded the expected 698-bp fragment amplified using rat MYH9-specific primers. Cochlear RNA, in the absence of RT, and water (H2O) served as negative controls. B, cDNA from all tissues tested for MYH9 expression. All samples are positive for expression of CYPR, a housekeeping gene, using CYPR-specific primers that yield the expected 371-bp fragment.
Figure 2
Figure 2
Immunolocalization of MYH9 in the rat cochlea. Radial sections of the rat cochlea were hybridized with anti-MYH9 antibody, were developed with a biotinylated, alkaline phosphatase–linked amplification system and were stained with NBT-BCIP. A, Photomicrograph of rat cochlear duct, illustrating the presence of anti-MYH9 immunoreactivity in several regions of the cochlea, including outer hair cells, cells of the organ of Corti (OC), the subcentral region of the spiral ligament (SL), and the Reissner membrane (RM). SGN = spiral ganglion neurons; SV = stria vascularis. B, The cochlear sections incubated without the anti-MYH9 antibody. The sections are free of immunoreactivity.
Figure 3
Figure 3
A, Pedigree with DFNA17. The affected members of five generations of the family with DFNA17 are denoted by blackened symbols. B, Sequence analysis of MYH9 in the family with DFNA17. MYH9 was sequenced in genomic DNA from the affected and unaffected members of the family with DFNA17. Although a single peak (G) is observed at nucleotide 2114 in the MYH9 sequence from the unaffected member V-2 (upper panel), a doublet (A/G) is observed at nucleotide 2114 (N) in the affected member III-4 (lower panel). The G→A transposition alters the codon from arginine (R) to histidine (H). C, Restriction analysis of MYH9 exon 16 2114G→A mutation eliminates the Fnu4HI restriction site, and this is reflected in the restriction digest pattern of MYH9 exon 16 from affected (III-4) and unaffected (V-2) individuals from the DFNA17 pedigree. The 284-bp PCR-amplified fragment contains three recognition sites for Fnu4HI—at 130, 135 and 168 bp from the 5′ end, of which the last site is absent in the mutant allele. Numbers at left are sizes of DNA ladder bands.
Figure 4
Figure 4
Alignment of the SH1 linker region in class II myosins. Alignment of peptide sequence spanning the SH1 linker region of muscle and nonmuscle class II myosins from seven species illustrates both the strict conservation of this linker region and the invariance of arginine (R705) in this sequence motif.
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References

Electronic-Database Information

    1. GenBank, http://www.ncbi.nlm.nih.gov/Genbank (for rat myh9 sequence [accession number GI 6981235])
    1. Genome Database, http://www.gdb.org
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/omim (for DFNA17 [MIM 603622])
    1. Primer3 software, http://www.genome.wi.mit.edu

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