RT Journal Article
SR Electronic
T1 Localization of PDZD7 to the Stereocilia Ankle-Link Associates this Scaffolding Protein with the Usher Syndrome Protein Network
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 14288
OP 14293
DO 10.1523/JNEUROSCI.3071-12.2012
VO 32
IS 41
A1 M'hamed Grati
A1 Jung-Bum Shin
A1 Michael D. Weston
A1 James Green
A1 Manzoor A. Bhat
A1 Peter G. Gillespie
A1 Bechara Kachar
YR 2012
UL http://www.jneurosci.org/content/32/41/14288.abstract
AB Usher syndrome is the leading cause of genetic deaf–blindness. Monoallelic mutations in PDZD7 increase the severity of Usher type II syndrome caused by mutations in USH2A and GPR98, which respectively encode usherin and GPR98. PDZ domain-containing 7 protein (PDZD7) is a paralog of the scaffolding proteins harmonin and whirlin, which are implicated in Usher type 1 and type 2 syndromes. While usherin and GPR98 have been reported to form hair cell stereocilia ankle-links, harmonin localizes to the stereocilia upper tip-link density and whirlin localizes to both tip and ankle-link regions. Here, we used mass spectrometry to show that PDZD7 is expressed in chick stereocilia at a comparable molecular abundance to GPR98. We also show by immunofluorescence and by overexpression of tagged proteins in rat and mouse hair cells that PDZD7 localizes to the ankle-link region, overlapping with usherin, whirlin, and GPR98. Finally, we show in LLC-PK1 cells that cytosolic domains of usherin and GPR98 can bind to both whirlin and PDZD7. These observations are consistent with PDZD7 being a modifier and candidate gene for USH2, and suggest that PDZD7 is a second scaffolding component of the ankle-link complex.