Loss of lysophosphatidylcholine acyltransferase 1 leads to photoreceptor degeneration in rd11 mice.
Document Type
Article
Publication Date
2010
Keywords
Base-Sequence, Blotting-Northern, Chromatography-High-Pressure-Liquid, Chromosome-Mapping, DNA-Mutational-Analysis, Humans, Immunoblotting, Leber-Congenital-Amaurosis, Lipids, Mice-Inbred-BALB-C, Mice-Inbred-C3H, Mice-Inbred-C57BL, Mice-Inbred-DBA, Mice-Inbred-Strains, Mice-Mutant-Strains, Microscopy-Electron-Transmission, Phosphatidylcholines, Photoreceptor-Cells-Vertebrate, Retinal-Degeneration, Retinitis-Pigmentosa, Reverse-Transcriptase-Polymerase-Chain-Reaction
First Page
15523
Last Page
15528
JAX Source
Proc Natl Acad Sci U S A 2010 Aug; 107(35):15523-8.
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.
Recommended Citation
Friedman JS,
Chang B,
Krauth DS,
Lopez I,
Liu C,
Bhattacharya SS,
Koenekoop RK,
Heckenlively JR,
et a.
Loss of lysophosphatidylcholine acyltransferase 1 leads to photoreceptor degeneration in rd11 mice. Proc Natl Acad Sci U S A 2010 Aug; 107(35):15523-8.