Loss of lysophosphatidylcholine acyltransferase 1 leads to photoreceptor degeneration in rd11 mice

James S Friedman; Hirva A Bakeri; Bo Chang; Shomi S Bhattacharya; Daniel S Krauth; Irma Lopez; Naushin H Waseem; Ron E Hurd; Kecia L Feathers; Kari E Branham; Manessa Shaw; George E Thomas; Matthew J Brooks; Chunqiao Liu; Maria M Campos; Cecilia Maubaret; Andrew R Webster; Ignacio R Rodriguez; Debra A Thompson; Robert K Koenekoop; John R Heckenlively; Anand Swaroop

doi:10.1073/pnas.1002897107

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Loss of lysophosphatidylcholine acyltransferase 1 leads to photoreceptor degeneration in rd11 mice

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Loss of lysophosphatidylcholine acyltransferase 1 leads to photoreceptor degeneration in rd11 mice

James S Friedman, Hirva A Bakeri, Bo Chang, Shomi S Bhattacharya, Daniel S Krauth, Irma Lopez, Naushin H Waseem, Ron E Hurd, Kecia L Feathers, Kari E Branham, …

Proceedings of the National Academy of Sciences - PNAS, Vol.107(35), pp.15523-15528

08/31/2010

DOI: 10.1073/pnas.1002897107

PMCID: PMC2932565

PMID: 20713727

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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.

Biological Sciences

visual dysfunction

retinal degeneration

phospholipid remodeling

gene discovery

lipid enzyme

Details

Title: Subtitle: Loss of lysophosphatidylcholine acyltransferase 1 leads to photoreceptor degeneration in rd11 mice
Creators: James S Friedman - Neurobiology-Neurodegeneration and Repair Laboratory
Hirva A Bakeri - Neurobiology-Neurodegeneration and Repair Laboratory
Bo Chang - , Bar Harbor, ME 04609
Shomi S Bhattacharya - Department of Genetics
Daniel S Krauth - Neurobiology-Neurodegeneration and Repair Laboratory
Irma Lopez - McGill Ocular Genetics Laboratory, Montreal Children's Hospital
Naushin H Waseem - Department of Genetics
Ron E Hurd - , Bar Harbor, ME 04609
Kecia L Feathers - Department of Ophthalmology and Visual Sciences
Kari E Branham - Department of Ophthalmology and Visual Sciences
Manessa Shaw - Department of Ophthalmology and Visual Sciences
George E Thomas - Department of Ophthalmology and Visual Sciences
Matthew J Brooks - Neurobiology-Neurodegeneration and Repair Laboratory
Chunqiao Liu - Neurobiology-Neurodegeneration and Repair Laboratory
Maria M Campos - Biological Imaging Core, and
Cecilia Maubaret - Department of Genetics
Andrew R Webster - Department of Genetics
Ignacio R Rodriguez - Mechanisms of Retinal Diseases Section, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute
Debra A Thompson - Department of Ophthalmology and Visual Sciences
Robert K Koenekoop - McGill Ocular Genetics Laboratory, Montreal Children's Hospital
John R Heckenlively - Department of Ophthalmology and Visual Sciences
Anand Swaroop - Neurobiology-Neurodegeneration and Repair Laboratory
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.107(35), pp.15523-15528
DOI: 10.1073/pnas.1002897107
PMID: 20713727
PMCID: PMC2932565
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Language: English
Date published: 08/31/2010
Academic Unit: General Internal Medicine; Internal Medicine
Record Identifier: 9984094380602771

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