The Usher Syndrome Proteins Cadherin 23 and Harmonin Form a Complex by Means of PDZ-domain Interactions

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2002 Oct 31

PMID 12407180

Citations 103

Authors

Jan Siemens

Piotr Kazmierczak

Anna Reynolds

Melanie Sticker

Amanda Littlewood-Evans

Ulrich Muller

Affiliations

Soon will be listed here.

Abstract

Usher syndrome type 1 (USH1) patients suffer from sensorineuronal deafness, vestibular dysfunction, and visual impairment. Several genetic loci have been linked to USH1, and four of the relevant genes have been identified. They encode the unconventional myosin VIIa, the PDZ-domain protein harmonin, and the putative adhesion receptors cadherin 23 (CDH23) and protocadherin 15 (PCDH15). We show here that CDH23 and harmonin form a protein complex. Two PDZ domains in harmonin interact with two complementary binding surfaces in the CDH23 cytoplasmic domain. One of the binding surfaces is disrupted by sequences encoded by an alternatively spliced CDH23 exon that is expressed in the ear, but not the retina. In the ear, CDH23 and harmonin are expressed in the stereocilia of hair cells, and in the retina within the photoreceptor cell layer. Because CDH23-deficient mice have splayed stereocilia, our data suggest that CDH23 and harmonin are part of a transmembrane complex that connects stereocilia into a bundle. Defects in the formation of this complex are predicted to disrupt stereocilia bundles and cause deafness in USH1 patients.

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References

Gillespie P, Walker R . Molecular basis of mechanosensory transduction. Nature. 2001; 413(6852):194-202. DOI: 10.1038/35093011. View

Yagi T, Takeichi M . Cadherin superfamily genes: functions, genomic organization, and neurologic diversity. Genes Dev. 2000; 14(10):1169-80. View

Gietz R, Woods R . Screening for protein-protein interactions in the yeast two-hybrid system. Methods Mol Biol. 2002; 185:471-86. DOI: 10.1385/1-59259-241-4:471. View

Di Palma F, Pellegrino R, Noben-Trauth K . Genomic structure, alternative splice forms and normal and mutant alleles of cadherin 23 (Cdh23). Gene. 2001; 281(1-2):31-41. DOI: 10.1016/s0378-1119(01)00761-2. View

Vaccaro P, Dente L . PDZ domains: troubles in classification. FEBS Lett. 2002; 512(1-3):345-9. DOI: 10.1016/s0014-5793(02)02220-2. View

Hone S, Smith R . Genetics of hearing impairment. Semin Neonatol. 2002; 6(6):531-41. DOI: 10.1053/siny.2001.0094. View

Corey D, Hudspeth A . Kinetics of the receptor current in bullfrog saccular hair cells. J Neurosci. 1983; 3(5):962-76. PMC: 6564517. View

Pickles J, Comis S, Osborne M . Cross-links between stereocilia in the guinea pig organ of Corti, and their possible relation to sensory transduction. Hear Res. 1984; 15(2):103-12. DOI: 10.1016/0378-5955(84)90041-8. View

Muller U, DOERFLER W . Fixation of the unmethylated or the 5'-CCGG-3' methylated adenovirus late E2A promoter-cat gene construct in the genome of hamster cells: gene expression and stability of methylation patterns. J Virol. 1987; 61(12):3710-20. PMC: 255983. DOI: 10.1128/JVI.61.12.3710-3720.1987. View

10.

Richardson G, Bartolami S, Russell I . Identification of a 275-kD protein associated with the apical surfaces of sensory hair cells in the avian inner ear. J Cell Biol. 1990; 110(4):1055-66. PMC: 2116079. DOI: 10.1083/jcb.110.4.1055. View

11.

Assad J, Shepherd G, Corey D . Tip-link integrity and mechanical transduction in vertebrate hair cells. Neuron. 1991; 7(6):985-94. DOI: 10.1016/0896-6273(91)90343-x. View

12.

Akiyama S, Yamada S, Yamada K, LaFlamme S . Transmembrane signal transduction by integrin cytoplasmic domains expressed in single-subunit chimeras. J Biol Chem. 1994; 269(23):15961-4. View

13.

Littlewood Evans A, Muller U . Stereocilia defects in the sensory hair cells of the inner ear in mice deficient in integrin alpha8beta1. Nat Genet. 2000; 24(4):424-8. DOI: 10.1038/74286. View

14.

Verpy E, Leibovici M, Zwaenepoel I, Liu X, Gal A, Salem N . A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C. Nat Genet. 2000; 26(1):51-5. DOI: 10.1038/79171. View

15.

Bitner-Glindzicz M, Lindley K, Rutland P, Blaydon D, Smith V, Milla P . A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene. Nat Genet. 2000; 26(1):56-60. DOI: 10.1038/79178. View

16.

Alagramam K, Wright C, Pawlowski K, Erway L, Stubbs L, Woychik R . Neuroepithelial defects of the inner ear in a new allele of the mouse mutation Ames waltzer. Hear Res. 2000; 148(1-2):181-91. DOI: 10.1016/s0378-5955(00)00152-0. View

17.

El-Amraoui A, Safieddine S, Nouaille S, Perfettini I, Lecuit M, Cossart P . Vezatin, a novel transmembrane protein, bridges myosin VIIA to the cadherin-catenins complex. EMBO J. 2000; 19(22):6020-9. PMC: 305826. DOI: 10.1093/emboj/19.22.6020. View

18.

Di Palma F, Holme R, Bryda E, Belyantseva I, Pellegrino R, Kachar B . Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D. Nat Genet. 2001; 27(1):103-7. DOI: 10.1038/83660. View

19.

Bolz H, von Brederlow B, Ramirez A, Bryda E, Kutsche K, Nothwang H . Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D. Nat Genet. 2001; 27(1):108-12. DOI: 10.1038/83667. View

20.

Bork J, Peters L, Bernstein S, Ahmed Z, Ness S, Polomeno R . Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23. Am J Hum Genet. 2000; 68(1):26-37. PMC: 1234923. DOI: 10.1086/316954. View