HGNC Approved Gene Symbol: LRAT
Cytogenetic location: 4q32.1 Genomic coordinates (GRCh38) : 4:154,740,838-154,753,120 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q32.1 | Leber congenital amaurosis 14 | 613341 | Autosomal recessive | 3 |
| Retinal dystrophy, early-onset severe | 613341 | Autosomal recessive | 3 | |
| Retinitis pigmentosa, juvenile | 613341 | Autosomal recessive | 3 |
Lecithin retinol acyltransferase (LRAT; EC 2.3.1.135) catalyzes the first of a series of reactions that take place in retinal pigment epithelium (RPE), by which the chromophore of the visual pigments, 11-cis retinal, is derived from vitamin A (all-trans-retinol).
By RT-PCR using human retinal pigment epithelium (RPE) RNA and degenerate oligonucleotides based on peptide sequences of the bovine LRAT protein, Ruiz et al. (1999) generated a partial cDNA encoding human LRAT. Using this partial cDNA to screen a human RPE cDNA library, they isolated the complete LRAT coding sequence. The predicted 230-amino acid human LRAT protein contains 2 putative transmembrane domains. Western blot analysis detected an approximately 25- to 26-kD LRAT protein in human RPE cells; the calculated molecular mass of LRAT is 25.3 kD. Northern blot analysis detected a major 5.0-kb LRAT transcript in several human tissues, particularly those known for their high vitamin A-processing activity. In fetal tissues, LRAT was expressed in the RPE and liver, and slightly in brain. In adult tissues, LRAT was expressed at the highest levels in testis and liver, followed by the RPE, small intestine, prostate, pancreas, and colon, and at a low level in brain. Additional smaller LRAT transcripts were also found in several tissues, and the authors suggested that these represent polyadenylation variants.
By fluorescence in situ hybridization and radiation hybrid mapping, Ruiz et al. (2001) localized the LRAT gene to chromosome 4q31.2.
Xue et al. (2004) showed that the membrane-associated form of RPE65 (mRPE65; 180069) is triply palmitoylated and is a chaperone for all-trans-retinyl esters, allowing their entry into the visual cycle for processing into 11-cis-retinal. The soluble form of RPE65 (sRPE65) is not palmitoylated and is a chaperone for vitamin A rather than all-trans-retinyl esters. Thus, the palmitoylation of RPE65 controls its ligand binding selectivity. The 2 chaperones are interconverted by LRAT acting as a molecular switch, with mRPE65 as the palmitoyl donor. When chromophore synthesis is not required, mRPE65 is converted into sRPE65 by LRAT, and further chromophore synthesis is blocked. The studies revealed novel roles for palmitoylated proteins as molecular switches and for LRAT as a palmitoyl transferase whose role is to catalyze the conversion of mRPE65 to sRPE65.
Thompson et al. (2001) screened 267 retinal dystrophy patients for mutations in the LRAT gene and identified disease-associated mutations ser175 to arg (S175R; 604863.0001) and 396delAA (604863.0002) in 3 individuals with severe, early-onset disease. They showed that the S175R mutant has no acyltransferase activity in transfected COS-7 cells. The findings highlighted the importance of genetic defects in vitamin A metabolism as causes of retinal dystrophies and extended prospects for retinoid replacement therapy in this group of diseases.
In a 21-month-old boy with Leber congenital amaurosis (LCA14; 613341), Senechal et al. (2006) screened the LRAT gene and identified homozygosity for a 2-bp deletion (217delAT; 604863.0003). The deletion was predicted to abrogate the production of retinyl esters and thus the formation of 11-cis retinol by RPE65; therefore, the deficiency in LRAT would have the same functional consequences as that in RPE65, e.g., the virtual absence of the chromophore 11-cis retinal with very few functional visual pigment molecules. Senechal et al. (2006) noted that the 'early-onset severe retinal dystrophy' described by Thompson et al. (2001) in 3 patients with mutations in the LRAT gene (see 604863.0001 and 604863.0002) was compatible with the clinical description of this LCA patient.
In 2 unrelated French Canadian probands, one diagnosed with LCA and the other with juvenile retinitis pigmentosa (see 613341), den Hollander et al. (2007) identified homozygosity for the same 2-bp deletion previously found by Senechal et al. (2006) in a French boy with LCA. Den Hollander et al. (2007) suggested that 217delAT might represent a founder mutation originating from France.
Inactivating mutations in the RPE65 and LRAT genes cause forms of Leber congenital amaurosis (LCA). Maeda et al. (2009) investigated human RPE65-LCA patients and mice with visual cycle abnormalities to determine the impact of chronic chromophore deprivation on cones. Young patients with RPE65 mutations showed foveal cone loss along with shortened inner and outer segments of remaining cones; cone cell loss also was dramatic in young mice lacking Rpe65 or Lrat gene function. To selectively evaluate cone pathophysiology, the authors eliminated the rod contribution to electroretinographic responses by generating double-knockout mice lacking Lrat or Rpe65 together with an inactivated Gnat1 gene (139330). Cone ERG responses were absent in Gnat1-null/Lrat-null mice, which also showed progressive degeneration of cones. Cone ERG responses in Gnat1-null/Rpe65-null mice were markedly reduced and declined over weeks. Treatment of these mice with an artificial chromophore prodrug, 9-cis-retinyl acetate, partially protected inferior retinal cones as evidenced by improved ERGs and retinal histochemistry. Gnat1-null mice chronically treated with retinylamine, a selective inhibitor of RPE65, also showed a decline in the number of cones that was ameliorated by 9-cis-retinyl acetate. Maeda et al. (2009) suggested that chronic lack of chromophore may lead to progressive loss of cones in mice and humans, and that therapy for LCA patients could be geared toward early adequate delivery of chromophore to cone photoreceptors.
In 2 patients, healthy other than for the presence of retinal dystrophy (see 613341), Thompson et al. (2001) found a homozygous ser175-to-arg (S175R) mutation in the LRAT gene. One patient was a 36-year-old woman who had had night blindness and poor vision as a child and was diagnosed with retinitis pigmentosa at 2 to 3 years of age. She had a visual field of less than 5 degrees. Her parents were second cousins. Both parents and a sib had normal vision. The second patient was a 23-year-old woman who had had night blindness and poor vision as a child and was diagnosed with retinitis pigmentosa at 7 years of age. The visual field was restricted to tiny central islands. Funduscopic examination showed optic disc pallor, attenuated retinal arterioles, peripheral RPE atrophy, and perimacular retinal surface wrinkling but little bone-spicule pigment.
In a patient with severe early-onset retinal dystrophy (see 613341), Thompson et al. (2001) found a heterozygous 2-bp deletion (396delAA) on the paternal allele of the LRAT gene that resulted in a shift of the reading frame after codon 133 to encode 11 amino acids unrelated to the wildtype sequence followed by a premature stop codon. The patient had nystagmus and was diagnosed with retinal degeneration at age 3. He had no electroretinogram responses at age 15 and at age 25 had no central vision. No other mutation was found, but it was considered likely that the maternal allele carried a mutation.
In a 21-month-old boy with Leber congenital amaurosis (LCA14; 613341), Senechal et al. (2006) identified homozygosity for a 2-bp deletion (217delAT) in the LRAT gene, causing a frameshift at codon 73 and a premature termination codon at residue 120. The deletion results in loss of tyr154 and cys161, essential for accepting the acyl group from lecithin; therefore, retinyl esters cannot be produced and the formation of 11-cis retinol by RPE65 (180069) is prevented. The unaffected first-cousin parents were heterozygous for the deletion, which was not found in 112 ethnically matched control chromosomes.
In 2 unrelated French Canadian probands, one diagnosed with LCA and the other with juvenile retinitis pigmentosa (see 613341), den Hollander et al. (2007) identified homozygosity for the same 2-bp deletion previously found by Senechal et al. (2006) in a French boy with LCA. Den Hollander et al. (2007) suggested that 217delAT might represent a founder mutation originating from France.
den Hollander, A. I., Lopez, I., Yzer, S., Zonneveld, M. N., Janssen, I. M., Strom, T. M., Hehir-Kwa, J. Y., Veltman, J. A., Arends, M. L., Meitinger, T., Musarella, M. A., van den Born, L. I., Fishman, G. A., Maumenee, I. H., Rohrschneider, K., Cremers, F. P. M., Koenekoop, R. K. Identification of novel mutations in patients with Leber congenital amaurosis and juvenile RP by genome-wide homozygosity mapping with SNP microarrays. Invest. Ophthal. Vis. Sci. 48: 5690-5698, 2007. [PubMed: 18055821] [Full Text: https://doi.org/10.1167/iovs.07-0610]
Maeda, T., Cideciyan, A. V., Maeda, A., Golczak, M., Aleman, T. S., Jacobson, S. G., Palczewski, K. Loss of cone photoreceptors caused by chromophore depletion is partially prevented by the artificial chromophore pro-drug, 9-cis-retinyl acetate. Hum. Molec. Genet. 18: 2277-2287, 2009. [PubMed: 19339306] [Full Text: https://doi.org/10.1093/hmg/ddp163]
Ruiz, A., Kuehn, M. H., Andorf, J. L., Stone, E., Hageman, G. S., Bok, D. Genomic organization and mutation analysis of the gene encoding lecithin retinol acyltransferase in human retinal pigment epithelium. Invest. Ophthal. Vis. Sci. 42: 31-37, 2001. [PubMed: 11133845]
Ruiz, A., Winston, A., Lim, Y.-H., Gilbert, B. A., Rando, R. R., Bok, D. Molecular and biochemical characterization of lecithin retinol acyltransferase. J. Biol. Chem. 274: 3834-3841, 1999. [PubMed: 9920938] [Full Text: https://doi.org/10.1074/jbc.274.6.3834]
Senechal, A., Humbert, G., Surget, M.-O., Bazalgette, C., Bazalgette, C., Arnaud, B., Arndt, C., Laurent, E., Brabet, P., Hamel, C. P. Screening genes of the retinoid metabolism: novel LRAT mutation in Leber congenital amaurosis. Am. J. Ophthal. 142: 702-704, 2006. [PubMed: 17011878] [Full Text: https://doi.org/10.1016/j.ajo.2006.04.057]
Thompson, D. A., Li, Y., McHenry, C. L., Carlson, T. J., Ding, X., Sieving, P. A., Apfelstedt-Sylla, E., Gal, A. Mutations in the gene encoding lecithin retinol acyltransferase are associated with early-onset severe retinal dystrophy. Nature Genet. 28: 123-124, 2001. [PubMed: 11381255] [Full Text: https://doi.org/10.1038/88828]
Xue, L., Gollapalli, D. R., Maiti, P., Jahng, W. J., Rando, R. R. A palmitoylation switch mechanism in the regulation of the visual cycle. Cell 117: 761-771, 2004. [PubMed: 15186777] [Full Text: https://doi.org/10.1016/j.cell.2004.05.016]