PMID- 20502675
OWN - NLM
STAT- MEDLINE
DCOM- 20100913
LR  - 20220224
IS  - 1553-7404 (Electronic)
IS  - 1553-7390 (Print)
IS  - 1553-7390 (Linking)
VI  - 6
IP  - 5
DP  - 2010 May 20
TI  - Ablation of whirlin long isoform disrupts the USH2 protein complex and causes 
      vision and hearing loss.
PG  - e1000955
LID - 10.1371/journal.pgen.1000955 [doi]
LID - e1000955
AB  - Mutations in whirlin cause either Usher syndrome type II (USH2), a 
      deafness-blindness disorder, or nonsyndromic deafness. The molecular basis for 
      the variable disease expression is unknown. We show here that only the whirlin 
      long isoform, distinct from a short isoform by virtue of having two N-terminal 
      PDZ domains, is expressed in the retina. Both long and short isoforms are 
      expressed in the inner ear. The N-terminal PDZ domains of the long whirlin 
      isoform mediates the formation of a multi-protein complex that includes usherin 
      and VLGR1, both of which are also implicated in USH2. We localized this USH2 
      protein complex to the periciliary membrane complex (PMC) in mouse photoreceptors 
      that appears analogous to the frog periciliary ridge complex. The latter is 
      proposed to play a role in photoreceptor protein trafficking through the 
      connecting cilium. Mice carrying a targeted disruption near the N-terminus of 
      whirlin manifest retinal and inner ear defects, reproducing the clinical features 
      of human USH2 disease. This is in contrast to mice with mutations affecting the 
      C-terminal portion of whirlin in which the phenotype is restricted to the inner 
      ear. In mice lacking any one of the USH2 proteins, the normal localization of all 
      USH2 proteins is disrupted, and there is evidence of protein destabilization. 
      Taken together, our findings provide new insights into the pathogenic mechanism 
      of Usher syndrome. First, the three USH2 proteins exist as an obligatory 
      functional complex in vivo, and loss of one USH2 protein is functionally close to 
      loss of all three. Second, defects in the three USH2 proteins share a common 
      pathogenic process, i.e., disruption of the PMC. Third, whirlin mutations that 
      ablate the N-terminal PDZ domains lead to Usher syndrome, but non-syndromic 
      hearing loss will result if they are spared.
FAU - Yang, Jun
AU  - Yang J
AD  - The Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard 
      Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, 
      United States of America.
FAU - Liu, Xiaoqing
AU  - Liu X
FAU - Zhao, Yun
AU  - Zhao Y
FAU - Adamian, Michael
AU  - Adamian M
FAU - Pawlyk, Basil
AU  - Pawlyk B
FAU - Sun, Xun
AU  - Sun X
FAU - McMillan, D Randy
AU  - McMillan DR
FAU - Liberman, M Charles
AU  - Liberman MC
FAU - Li, Tiansen
AU  - Li T
LA  - eng
GR  - R01 EY10309/EY/NEI NIH HHS/United States
GR  - R01 DC00188/DC/NIDCD NIH HHS/United States
GR  - P30 DC005209/DC/NIDCD NIH HHS/United States
GR  - P30 EY014104/EY/NEI NIH HHS/United States
GR  - R01 EY010309/EY/NEI NIH HHS/United States
GR  - R01 DC000188/DC/NIDCD NIH HHS/United States
GR  - P30 DC05209/DC/NIDCD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100520
PL  - United States
TA  - PLoS Genet
JT  - PLoS genetics
JID - 101239074
RN  - 0 (Extracellular Matrix Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Protein Isoforms)
RN  - 0 (USH2A protein, human)
RN  - 0 (Whrn protein, mouse)
SB  - IM
MH  - Animals
MH  - Extracellular Matrix Proteins/genetics/*physiology
MH  - Hearing Loss/*genetics
MH  - Membrane Proteins/genetics/*physiology
MH  - Mice
MH  - Mice, Knockout
MH  - Protein Isoforms/genetics/*physiology
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Vision Disorders/*genetics
PMC - PMC2873905
COIS- The authors have declared that no competing interests exist.
EDAT- 2010/05/27 06:00
MHDA- 2010/09/14 06:00
PMCR- 2010/05/01
CRDT- 2010/05/27 06:00
PHST- 2009/12/21 00:00 [received]
PHST- 2010/04/19 00:00 [accepted]
PHST- 2010/05/27 06:00 [entrez]
PHST- 2010/05/27 06:00 [pubmed]
PHST- 2010/09/14 06:00 [medline]
PHST- 2010/05/01 00:00 [pmc-release]
AID - 09-PLGE-RA-2244R2 [pii]
AID - 10.1371/journal.pgen.1000955 [doi]
PST - epublish
SO  - PLoS Genet. 2010 May 20;6(5):e1000955. doi: 10.1371/journal.pgen.1000955.