The Usher syndrome proteins cadherin 23 and harmonin form a complex by means of PDZ-domain interactions.
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.
Siemens
Jan
J
Friedrich Miescher Institute, Maulbeerstrasse 66, 4058 Basel, Switzerland.
Kazmierczak
Piotr
P
Reynolds
Anna
A
Sticker
Melanie
M
Littlewood-Evans
Amanda
A
Müller
Ulrich
U
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015820:Cadherins / Q000235:genetics* / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D007106:Immune Sera; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011485:Protein Binding; D011817:Rabbits; D012174:Retinitis Pigmentosa / Q000235:genetics*; D013577:Syndrome
D015820:Cadherins; D002352:Carrier Proteins; C499091:Cdh23 protein, mouse; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D007106:Immune Sera; C492262:Ush1c protein, mouse