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.etinitis pigmentosa (RP) constitutes a group of common inherited retinal dystrophies with clinical manifestations, including nyctalopia (night blindness) and loss of peripheral vision. One of the early hallmarks of RP is photoreceptor dysfunction that is followed by the death of rod and then cone photoreceptors. To date, over 40 genes have been associated with inherited forms of RP (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).Animal models of retinal degeneration are a valuable resource in elucidation of genes for human retinal diseases, including RP and Leber congenital amaurosis (LCA) (4, 5). One of the first mouse retinal degeneration lines examined, rd1, was defective in Pde6b, encoding β-subunit of cGMP phosphodiesterase and was determined to have both an insertion and a point mutation (6, 7). The rd7 mouse line resulted from the loss of function of orphan nuclear receptor NR2E3 (8, 9), and rd16 mice carried an in-frame deletion in the broadly expressed Cep290 (10). Cross-species mutation discovery rapidly occurred in each case once the initial disease causing...

Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness

“…Interestingly and importantly, we show a significant accumulation of all, LPA, LPC and LC, which may explain some of the clinical features of OMS. Indeed, elevated concentrations of LPA are known to be cytotoxic to neuronal cells, including photoreceptors 21 , and defects in the LPC acyltransferase-1, an enzyme catalysing the conversion of LPC to PC, cause photoreceptor degeneration in mice 22 . LPA also promotes hair growth 23 and defects either in LPA production 24,25 or LPA signalling 26,27 are associated with hair growth abnormalities, as observed in our OMS patients.…”

Lysophospholipid acyltransferases

“…In another study, the loss of LPCAT1 resulted in the degeneration of photoreceptors in mice lacking the rd11 locus [40]. However, no mutation was found in the limited human cohorts of two phenotypically similar diseases, retinitis pigmentosa and Leber congenital amaurosis (LCA) [40]. However, it remains a strong candidate gene given the importance of phospholipids in the biology of photoreceptors.…”

“…In these animals, decreased saturated phosphatidylcholine content was observed in their surfactant, suggesting that adequate saturated phosphatidylcholine is essential for the transition to air breathing. In another study, the loss of LPCAT1 resulted in the degeneration of photoreceptors in mice lacking the rd11 locus [40]. However, no mutation was found in the limited human cohorts of two phenotypically similar diseases, retinitis pigmentosa and Leber congenital amaurosis (LCA) [40].…”

LPS Impairs Phospholipid Synthesis by Triggering β-Transducin Repeat-containing Protein (β-TrCP)-mediated Polyubiquitination and Degradation of the Surfactant Enzyme Acyl-CoA:Lysophosphatidylcholine Acyltransferase I (LPCAT1)

“…These results are intriguing as they suggest that LPCAT1 might also harbor upstream phosphoacceptor sites that differentially regulate its enzymatic behavior after endotoxin. Interestingly, another recent study showed that a mutation in exon 3 of the Lpcat1 gene leads to generation of an LPCAT1 variant linked to reduced DPPtdCho and photoreceptor dysfunction in the retina (27). Because this LPCAT1 variant is nonfunctional and truncated (with a stop after residue 178, size ϳ20 kDa), it also is likely eliminated but by unknown mechanisms given that it lacks the ubiquitin acceptor site.…”