Novel mechanism of massive photoreceptor degeneration caused by mutations in the trp gene of Drosophila.
The Drosophila trp gene encodes a light-activated Ca(2+) channel subunit, which is a prototypical member of a novel class of channel proteins. Previously identified trp mutants are all recessive, loss-of-function mutants characterized by a transient receptor potential and the total or near-total loss of functional TRP protein. Although retinal degeneration does occur in these mutants, it is relatively mild and slow in onset. We report herein a new mutant, Trp(P365), that does not display the transient receptor potential phenotype and is characterized by a substantial level of the TRP protein and rapid, semi-dominant degeneration of photoreceptors. We show that, in spite of its unusual phenotypes, Trp(P365) is a trp allele because a Trp(P365) transgene induces the mutant phenotype in a wild-type background, and a wild-type trp transgene in a Trp(P365) background suppresses the mutant phenotype. Moreover, amino acid alterations that could cause the Trp(P365) phenotype are found in the transmembrane segment region of the mutant channel protein. Whole-cell recordings clarified the mechanism underlying the retinal degeneration by showing that the TRP channels of Trp(P365) are constitutively active. Although several genes, when mutated, have been shown to cause retinal degeneration in Drosophila, the underlying mechanism has not been identified for any of them. The present studies provide evidence for a specific mechanism for massive degeneration of photoreceptors in Drosophila. Insofar as some human homologs of TRP are highly expressed in the brain, a similar mechanism could be a major contributor to degenerative disorders of the brain.
Yoon
J
J
Institute of Genetic Engineering and Natural Sciences, Department of Genetic Engineering, KyungHee University, Yongin City, Kyungki-Do, 449-701 Korea.
Ben-Ami
H C
HC
Hong
Y S
YS
Park
S
S
Strong
L L
LL
Bowman
J
J
Geng
C
C
Baek
K
K
Minke
B
B
Pak
W L
WL
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D004331:Drosophila melanogaster / Q000235:genetics* / Q000502:physiology; D004596:Electroretinography; D017344:Genes, Insect; D006801:Humans; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009410:Nerve Degeneration / Q000235:genetics; D010641:Phenotype; D017956:Photoreceptor Cells, Invertebrate / Q000166:cytology* / Q000502:physiology*; D017354:Point Mutation; D012160:Retina / Q000648:ultrastructure; D050052:TRPC Cation Channels
D015220:Calcium Channels; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1