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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 Loss of lysophosphatidylcholine acyltransferase 1 leads to photoreceptor degeneration in rd11 mice James S. Friedmana, Bo Changb, Daniel S. Krautha, Irma Lopezc, Naushin H. Waseemd, Ron E. Hurdb, Kecia L. Featherse, Kari E. Branhame, Manessa Shawe, George E. Thomase, Matthew J. Brooksa, Chunqiao Liua, Hirva A. Bakeria, Maria M. Camposf, Cecilia Maubaretd, Andrew R. Websterd, Ignacio R. Rodriguezg, Debra A. Thompsone, Shomi S. Bhattacharyad, Robert K. Koenekoopc, John R. Heckenlivelye, and Anand Swaroopa,e,1 aNeurobiology-Neurodegeneration and Repair Laboratory, fBiological Imaging Core, and gMechanisms of Retinal Diseases Section, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892; bThe Jackson Laboratory, Bar Harbor, ME 04609; cMcGill Ocular Genetics Laboratory, Montreal Children’s Hospital, McGill University Health Centre, Montreal, Quebec H3H-1P3, Canada; dDepartment of Genetics, University College London Institute of Ophthalmology, London EC1V 9EL, United Kingdom; and eDepartment of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105 Edited by Jeremy Nathans, Johns Hopkins University, Baltimore, MD, and approved July 26, 2010 (received for review March 9, 2010) Retinal degenerative diseases, such as retinitis pigmentosa and (11–13). The study of proteins encoded by these genes is leading Leber congenital amaurosis, are a leading cause of untreatable to a better understanding of the visual transduction pathway, blindness with substantive impact on the quality of life of affected transcription, and ciliogenesis, respectively. individuals and their families. Mouse mutants with retinal dystro- In our ongoing effort to uncover genes critical for retinal func- rd11 JR2845 phies have provided a valuable resource to discover human disease tion or disease, we examined the and B6- strains of genes and helped uncover pathways critical for photoreceptor func- mice that were reported to exhibit retinal degeneration (4). Here tion. Here we show that the rd11 mouse mutant and its allelic strain, we describe the detailed retinal phenotype of these mouse mutants, followed by mapping of the disease locus, and identifi- B6-JR2845, exhibit rapid photoreceptor dysfunction, followed by de- cation of mutations in the Lpcat1 gene that encodes a phospholipid generation of both rods and cones. Using linkage analysis, we map- remodeling enzyme, lysophosphatidylcholine (LPC) acyltransfer- ped the rd11 locus to mouse chromosome 13. We then identified Lpcat1 GENETICS – Lpcat1 ase (AT). To assess the physiological impact of mutations, a one-nucleotide insertion (c.420 421insG) in exon 3 of the we have examined membrane association of retinal pigment epi- JR2845 gene. Subsequent screening of this gene in the B6- strain thelium 65-kDa protein (RPE65), measured retinyl ester content, revealed a seven-nucleotide deletion (c.14–20delGCCGCGG) in exon and evaluated dipalmitoylphosphatidylcholine (DPPC), the down- 1. Both sequence changes are predicted to result in a frame-shift, stream product of LPCAT1 enzyme, in rd11 and B6-JR2845 ret- leading to premature truncation of the lysophosphatidylcholine ina. We also report the screening of LPCAT1 in patients with acyltransferase-1 (LPCAT1) protein. LPCAT1 (also called AYTL2) is human retinopathy. a phospholipid biosynthesis/remodeling enzyme that facilitates the conversion of palmitoyl-lysophosphatidylcholine to dipalmitoyl- Results phosphatidylcholine (DPPC). The analysis of retinal lipids from rd11 Retinal Phenotype of the rd11 and B6-JR2845 Mutant Mice. The rd11 and B6-JR2845 mice showed substantially reduced DPPC levels com- and B6-JR2845 strains of mice were identified at The Jackson pared with C57BL/6J control mice, suggesting a causal link to photo- Laboratory in a screen for naturally occurring mouse models of receptor dysfunction. A follow-up screening of LPCAT1 in retinitis retinal disease (4). The two strains are genetically allelic by com- pigmentosa and Leber congenital amaurosis patients did not reveal plementation analysis and do not show any other obvious mor- any obvious disease-causing mutations. Previously, LPCAT1 has been phological or functional phenotype. Retinal fundus examination suggested to be critical for the production of lung surfactant phos- revealed a similar phenotype between both strains. Retinal vessels fl became attenuated by postnatal (P) day 36 with retinal de- pholipids and biosynthesis of platelet-activating factor in nonin am- A matory remodeling pathway. Our studies add another dimension to generation obvious by P113 (Fig. 1 ). Electroretinograms (ERGs) of rd11 mice presented with a reduced rod photoreceptor (dark- an essential role for LPCAT1 in retinal photoreceptor homeostasis. adapted) a-wave, which flattened out at 4 wk of age. Cone pho- toreceptor (light-adapted) response was similar to WT at 3 wk, but gene discovery | lipid enzyme | phospholipid remodeling | retinal was reduced substantially at 4 and 5 wk. These results suggest that degeneration | visual dysfunction rod photoreceptors are affected before cones (Fig. 1B), consistent with a retinitis pigmentosa-like phenotype. A similar fundus and etinitis pigmentosa (RP) constitutes a group of common ERG profile was observed with B6-JR2845 mice (Fig. S1). Rinherited retinal dystrophies with clinical manifestations, in- Histologically, photoreceptors appeared to develop normally cluding nyctalopia (night blindness) and loss of peripheral vision. in both strains of mice. At P21, no substantial degeneration was One of the early hallmarks of RP is photoreceptor dysfunction that observed in rd11 mice. However, rapid photoreceptor de- is followed by the death of rod and then cone photoreceptors. To generation was seen after P21. By P31, only four to five rows of date, over 40 genes have been associated with inherited forms of RP photoreceptor nuclei were present instead of the usual 10 to 12 (Retnet: www.sph.uth.tmc.edu/retnet/); these genes exhibit distinct patterns of expression (e.g., rod-specific or widely expressed) and encode proteins of diverse biological functions (1–3). Author contributions: J.S.F., B.C., D.S.K., D.A.T., S.S.B., R.K.K., J.R.H., and A.S. designed Animal models of retinal degeneration are a valuable resource research; J.S.F., B.C., D.S.K., I.L., N.H.W., R.E.H., K.L.F., M.S., G.E.T., M.J.B., C.L., H.A.B., in elucidation of genes for human retinal diseases, including RP M.M.C., C.M., and I.R.R. performed research; K.E.B., A.R.W., I.R.R., D.A.T., S.S.B., R.K.K., and Leber congenital amaurosis (LCA) (4, 5). One of the first and J.R.H. contributed new reagents/analytic tools; J.S.F., B.C., I.L., N.H.W., R.E.H., K.L.F., mouse retinal degeneration lines examined, rd1, was defective in M.S., G.E.T., M.J.B., C.L., C.M., I.R.R., D.A.T., S.S.B., R.K.K., and A.S. analyzed data; and J.S.F. Pde6b β and A.S. wrote the paper. , encoding -subunit of cGMP phosphodiesterase and was fl determined to have both an insertion and a point mutation (6, 7). The authors declare no con ict of interest. The rd7 mouse line resulted from the loss of function of orphan This article is a PNAS Direct Submission. nuclear receptor NR2E3 (8, 9), and rd16 mice carried an in-frame Freely available online through the PNAS open access option. deletion in the broadly expressed Cep290 (10). Cross-species 1To whom correspondence should be addressed. E-mail: [email protected]. mutation discovery rapidly occurred in each case once the initial This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. disease causing change (in either mice or humans) was identified 1073/pnas.1002897107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1002897107 PNAS Early Edition | 1of6 Downloaded by guest on September 24, 2021 Fig. 1. Photoreceptor degeneration and loss of ERG signal was observed in rd11 and B6-JR2845 mice. (A) Fundus image of rd11 mice at 24, 36, 113, and 180 d postnatal. Attenuated blood vessels were observed by P36. Large white patches of degeneration are seen by P133. A similar finding was observed in B6- Fig. 2. Photoreceptor disk formation is present in rd11 and B6-JR2845 mice. JR2845 mice (Fig. S1). (B) ERG examination of C57BL/6J (B6) WT at 4 wk of age Retinas from C57BL/6J (B6), rd11, and B6-JR2845 mice were examined by and rd11 mice at 3, 4, and 5 wk. Dark-adapted ERG showed a reduced a-wave in TEM. (A) Nuclei and rod photoreceptor structure appeared to be less densely rd11 mice at 3 wk of age, with a flattening of signal by 4 wk. Light-adapted ERG arranged in mutant mice than in WT (B6). (B) Photoreceptor outer segments was closer to WT at 3 wk of age but showed a substantial reduction of intensity were made in both rd11 and B6-JR2845 mice, suggesting that the mutation at 4 and 5 wk of age. B6-JR2845 mice revealed a similar pattern (Fig. S1). (C) observed did not have an effect on the generation of this structure. H&E staining of rd11,B6-JR2845, and B6 retinas. A substantial loss of photo- receptor nuclei was observed by P31, with a loss to one row of nuclei at P47 in (heart, brain, liver, skeletal muscle, kidney, and pancreas) with rd11 mice. B6-JR2845 photoreceptor nuclei were also obviously reduced by P31, maximum expression in placenta and lung (Fig. S3). Lpcat1 tran- although more nuclei were present at P47 than in rd11 mice. scripts were detectable by RT-PCR in GFP-tagged flow-sorted rod photoreceptors and in mouse retina from embryonic day 12 rows. At P47, only a single row of nuclei remained (Fig. 1C). B6- through 4 mo. (Fig. S3). Quantitative RT-PCR (qRT-PCR) of JR2845 mice demonstrated a similar pattern of degeneration; laser capture microdissected nuclei from retinal outer, inner, and however, more than one row of nuclei was still present by P47 ganglion cell layers suggested broad expression of Lpcat1 in mouse (Fig.
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