A novel form of transducin-dependent retinal degeneration: accelerated retinal degeneration in the absence of rod transducin.
OBJECTIVE
Rhodopsin mutations account for approximately 25% of human autosomal dominant retinal degenerations. However, the molecular mechanisms by which rhodopsin mutations cause photoreceptor cell death are unclear. Mutations in genes involved in the termination of rhodopsin signaling activity have been shown to cause degeneration by persistent activation of the phototransduction cascade. This study examined whether three disease-associated rhodopsin substitutions Pro347Ser, Lys296Glu, and the triple mutant Val20Gly, Pro23His, Pro27Leu (VPP) caused degeneration by persistent transducin-mediated signaling activity.


METHODS
Transgenic mice expressing each of the rhodopsin mutants were crossed onto a transducin alpha-subunit null (Tr(alpha)(-/-)) background, and the rates of photoreceptor degeneration were compared with those of transgenic mice on a wild-type background.


RESULTS
Mice expressing VPP-substituted rhodopsin had the same severity of degeneration in the presence or absence of Tr(alpha). Unexpectedly, mice expressing Pro347Ser- or Lys296Glu-substituted rhodopsins exhibited faster degeneration on a Tr(alpha)(-/-) background. To test whether the absence of alpha-transducin contributed to degeneration by favoring the formation of stable rhodopsin/arrestin complexes, mutant Pro347Ser(+), Tr(alpha)(-/-) mice lacking arrestin (Arr(-/-)) were analyzed. Rhodopsin/arrestin complexes were found not to contribute to degeneration.


CONCLUSIONS
The authors hypothesized that the decay of metarhodopsin to apo-opsin and free all-trans-retinaldehyde is faster with Pro347Ser-substituted rhodopsin than it is with wild-type rhodopsin. Consistent with this, the lipofuscin fluorophores A2PE, A2E, and A2PE-H(2), which form from retinaldehyde, were elevated in Pro347Ser transgenic mice.
Brill
Elliott
E
Molecular Cardiology Research Institute, Tufts New England Medical Center, Boston, Massachusetts, USA.
Malanson
Katherine M
KM
Radu
Roxana A
RA
Boukharov
Natalia V
NV
Wang
Zhongyan
Z
Chung
Hae-Yun
HY
Lloyd
Marcia B
MB
Bok
Dean
D
Travis
Gabriel H
GH
Obin
Martin
M
Lem
Janis
J
D000818:Animals; D019393:Arrestin / Q000235:genetics; D005838:Genotype; D008062:Lipofuscin / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000235:genetics*; D017354:Point Mutation; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism*; D012243:Rhodopsin / Q000235:genetics*; D015293:Transducin / Q000235:genetics*; D014785:Vision, Ocular
D019393:Arrestin; D008062:Lipofuscin; D009842:Oligopeptides; C489031:valyl-prolyl-proline; D012243:Rhodopsin; D015293:Transducin