title: Loss of lysophosphatidylcholine acyltransferase 1 leads to photoreceptor degeneration in rd11 mice.
abstract: 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.
authors: 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.
authors: James S
authors: JS
authors: Friedman
authors: Bo
authors: B
authors: Chang
authors: Daniel S
authors: DS
authors: Krauth
authors: Irma
authors: I
authors: Lopez
authors: Naushin H
authors: NH
authors: Waseem
authors: Ron E
authors: RE
authors: Hurd
authors: Kecia L
authors: KL
authors: Feathers
authors: Kari E
authors: KE
authors: Branham
authors: Manessa
authors: M
authors: Shaw
authors: George E
authors: GE
authors: Thomas
authors: Matthew J
authors: MJ
authors: Brooks
authors: Chunqiao
authors: C
authors: Liu
authors: Hirva A
authors: HA
authors: Bakeri
authors: Maria M
authors: MM
authors: Campos
authors: Cecilia
authors: C
authors: Maubaret
authors: Andrew R
authors: AR
authors: Webster
authors: Ignacio R
authors: IR
authors: Rodriguez
authors: Debra A
authors: DA
authors: Thompson
authors: Shomi S
authors: SS
authors: Bhattacharya
authors: Robert K
authors: RK
authors: Koenekoop
authors: John R
authors: JR
authors: Heckenlively
authors: Anand
authors: A
authors: Swaroop
mesh_terms: 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
chemical_list: D008055:Lipids; D010713:Phosphatidylcholines; D008243:1-Acylglycerophosphocholine O-Acyltransferase; C526202:Lpcat1 protein, human; C526203:Lpcat1 protein, mouse