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LRAT
lecithin retinol acyltransferase
LRAT is located on the long (q) arm of chromosome 4, at band 4q32.1. Arm ratio per GRCh38 - banding schematic.
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Overview
LRAT encodes lecithin retinol acyltransferase, an enzyme expressed predominantly in the retinal pigment epithelium of the eye. This protein is essential for the visual cycle, the biochemical pathway that enables photoreceptor cells to detect light and regenerate the light-sensitive molecule required for vision. The enzyme catalyses the esterification of all-trans-retinol, converting vitamin A into a storage form that can be mobilised when needed for visual pigment regeneration.
Pathogenic variants in LRAT disrupt vitamin A metabolism in the retina, preventing the formation of functional visual pigments. These changes are associated with inherited retinal disorders that can present in infancy or early childhood. The gene is located on chromosome 4 and is recognised in NHS clinical genomics pathways for retinal disease.
What the gene does
Lecithin retinol acyltransferase functions as the principal enzyme responsible for esterifying retinol in the retinal pigment epithelium. The protein uses phosphatidylcholine as an acyl donor to convert all-trans-retinol into retinyl esters, creating a reservoir of stored vitamin A within the eye. These retinyl esters serve as substrate for the visual cycle, the multi-step enzymatic pathway that regenerates 11-cis-retinal, the chromophore bound to opsin proteins in photoreceptor outer segments.
Without functional LRAT activity, the retina cannot maintain adequate stores of retinoid precursors, leading to progressive depletion of visual pigments in rod and cone photoreceptors. The enzyme is highly selective for all-trans-retinol and exhibits optimal activity in the lipid-rich environment of the retinal pigment epithelium. LRAT-mediated esterification represents the committed step in retinoid storage and is subject to feedback regulation based on cellular retinoid levels, ensuring appropriate balance between stored and bioavailable forms of vitamin A.
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Chromosome location
LRAT is located on the long arm of chromosome 4 at position 32.1 (4q32.1). The gene spans a relatively compact genomic region and encodes a single primary transcript. Its chromosomal position places it in a region that has been mapped in studies of retinal disease inheritance patterns.
Protein structure
The LRAT protein comprises 230 amino acids and contains a functionally characterised LRAT domain extending from amino acid 50 to 177. This domain encompasses the catalytic core responsible for the acyltransferase activity that drives retinyl ester synthesis. The protein adopts a membrane-associated configuration, anchoring to the endoplasmic reticulum within retinal pigment epithelial cells where it can access both lipid substrates and retinol delivered from the circulation. Structural studies suggest the active site is positioned to facilitate efficient transfer of fatty acyl groups from phosphatidylcholine to the hydroxyl group of retinol, forming the ester bond characteristic of stored vitamin A.
Key variants
Pathogenic variants in LRAT typically result in loss of enzyme function, impairing the retina's capacity to store vitamin A. These changes may include missense substitutions that destabilise the protein or disrupt catalytic residues, as well as nonsense and frameshift variants that lead to truncated, non-functional products. The clinical consequences of LRAT variants depend on the degree of residual enzyme activity, with complete loss of function generally associated with earlier onset and more severe retinal degeneration.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.12del | p.Met5fs | Pathogenic | ★★☆☆ | Retinal dystrophy |
c.139C>T | p.Arg47Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Leber congenital amaurosis 14 |
c.157_159dup | p.Val53dup | Pathogenic | ★★☆☆ | Leber congenital amaurosis 14 |
c.163C>G | p.Arg55Gly | Pathogenic/Likely pathogenic | ★★☆☆ | Leber congenital amaurosis 1 |
c.163C>T | p.Arg55Trp | Pathogenic | ★★☆☆ | Leber congenital amaurosis |
c.217_218del | p.Met73fs | Pathogenic/Likely pathogenic | ★★☆☆ | LRAT-related disorder |
c.459dup | p.Tyr154fs | Pathogenic/Likely pathogenic | ★★☆☆ | LRAT-related disorder |
c.504C>A | p.Cys168Ter | Pathogenic | ★★☆☆ | Leber congenital amaurosis 14 |
c.105_108del | p.Arg36fs | Pathogenic | ★☆☆☆ | not provided |
c.519del | p.Ile174fs | Pathogenic | ★☆☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in LRAT are associated with inherited retinal disorders characterised by progressive vision loss. These conditions typically present in infancy or early childhood with night blindness and visual field constriction, reflecting the early involvement of rod photoreceptors. Over time, cone photoreceptors may also be affected, leading to reduced central vision and colour perception. The spectrum of retinal phenotypes linked to LRAT dysfunction ranges from severe early-onset presentations to milder, later-onset forms, reflecting differences in residual enzyme activity and genetic background.
No disease links recorded for this gene in our reference set.
UK clinical status
LRAT is included in the NHS Genomic Medicine Service's retinal disorders panel with a green classification (confidence level R32), indicating strong evidence for its role in inherited eye disease. The gene also appears in the Developmental Disorders Genotype-to-Phenotype database (DDG2P) with green status, reflecting its established association with developmental visual impairment. These panel memberships support the use of LRAT genetic testing in NHS clinical pathways for individuals presenting with early-onset retinal degeneration or unexplained visual dysfunction in childhood.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the LRAT gene do?
LRAT encodes an enzyme that stores vitamin A in the retina by converting retinol into retinyl esters. This stored vitamin A is essential for regenerating the light-sensitive molecules in photoreceptor cells, enabling normal vision.
How are LRAT variants inherited?
LRAT-related retinal conditions typically follow an autosomal recessive pattern, meaning an individual must inherit pathogenic variants from both parents to develop the condition. Carriers with one variant copy generally have normal vision.
Can LRAT-related vision loss be prevented?
Currently, there is no established method to prevent retinal degeneration caused by LRAT variants. Research into retinoid supplementation and gene-based therapies is ongoing, but these approaches remain investigational and should only be pursued under specialist ophthalmology guidance.