Loss of lysophosphatidylcholine acyltransferase 1 leads to photoreceptor degeneration in rd11 mice.
Retinal degenerative diseases, such as retinitis pigmentosa and Leber congenital amaurosis, are a leading cause of untreatable blindness with substantive impact on the quality of life of affected individuals and their families. Mouse mutants with retinal dystrophies have provided a valuable resource to discover human disease genes and helped uncover pathways critical for photoreceptor function. Here we show that the rd11 mouse mutant and its allelic strain, B6-JR2845, exhibit rapid photoreceptor dysfunction, followed by degeneration of both rods and cones. Using linkage analysis, we mapped the rd11 locus to mouse chromosome 13. We then identified a one-nucleotide insertion (c.420-421insG) in exon 3 of the Lpcat1 gene. Subsequent screening of this gene in the B6-JR2845 strain revealed a seven-nucleotide deletion (c.14-20delGCCGCGG) in exon 1. Both sequence changes are predicted to result in a frame-shift, leading to premature truncation of the lysophosphatidylcholine acyltransferase-1 (LPCAT1) protein. LPCAT1 (also called AYTL2) is a phospholipid biosynthesis/remodeling enzyme that facilitates the conversion of palmitoyl-lysophosphatidylcholine to dipalmitoylphosphatidylcholine (DPPC). The analysis of retinal lipids from rd11 and B6-JR2845 mice showed substantially reduced DPPC levels compared with C57BL/6J control mice, suggesting a causal link to photoreceptor dysfunction. A follow-up screening of LPCAT1 in retinitis pigmentosa and Leber congenital amaurosis patients did not reveal any obvious disease-causing mutations. Previously, LPCAT1 has been suggested to be critical for the production of lung surfactant phospholipids and biosynthesis of platelet-activating factor in noninflammatory remodeling pathway. Our studies add another dimension to an essential role for LPCAT1 in retinal photoreceptor homeostasis.
Friedman
James S
JS
Neurobiology-Neurodegeneration and Repair Laboratory, Biological Imaging Core, and Mechanisms of Retinal Diseases Section, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Chang
Bo
B
Krauth
Daniel S
DS
Lopez
Irma
I
Waseem
Naushin H
NH
Hurd
Ron E
RE
Feathers
Kecia L
KL
Branham
Kari E
KE
Shaw
Manessa
M
Thomas
George E
GE
Brooks
Matthew J
MJ
Liu
Chunqiao
C
Bakeri
Hirva A
HA
Campos
Maria M
MM
Maubaret
Cecilia
C
Webster
Andrew R
AR
Rodriguez
Ignacio R
IR
Thompson
Debra A
DA
Bhattacharya
Shomi S
SS
Koenekoop
Robert K
RK
Heckenlively
John R
JR
Swaroop
Anand
A
D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002851:Chromatography, High Pressure Liquid; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D006801:Humans; D015151:Immunoblotting; D057130:Leber Congenital Amaurosis / Q000235:genetics; D008055:Lipids / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D046529:Microscopy, Electron, Transmission; D010713:Phosphatidylcholines / Q000032:analysis; D020419:Photoreceptor Cells, Vertebrate / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D008055:Lipids; D010713:Phosphatidylcholines; D008243:1-Acylglycerophosphocholine O-Acyltransferase; C526202:Lpcat1 protein, human; C526203:Lpcat1 protein, mouse