LRAT – Leber congenital amaurosis

Leber congenital amaurosis (LCA) is a severe autosomal recessive retinal dystrophy presenting with profound visual impairment from birth. LRAT encodes lecithin retinol acyltransferase, a critical enzyme in the vitamin A cycle that produces the 11-cis-retinal chromophore in the retinal pigment epithelium. Biallelic pathogenic LRAT variants disrupt chromophore synthesis, leading to early-onset photoreceptor degeneration.

Initial screening of 267 retinal dystrophy patients identified two pathogenic LRAT alleles (p.Ser175Arg and a frameshift) in three unrelated individuals with severe, early-onset disease (PMID:11381255). A subsequent targeted APEX microarray in 149 LCA/EOSRD patients uncovered four further homozygous LRAT variants in exon 2 in distinct LCA probands (PMID:22570351). Homozygosity mapping in a consanguineous cohort revealed an additional LRAT frameshift (c.217_218del, p.Met73fs) segregating with disease in one LCA family (PMID:18055821).

Segregation analysis in the homozygosity‐mapping family confirmed perfect cosegregation of the LRAT frameshift allele with LCA in multiple affected relatives (PMID:18055821).

To date, at least seven pathogenic LRAT variants have been described, including five missense substitutions (p.Ser175Arg, p.Tyr61Asn, p.Ala106Thr, p.Gly66Arg, p.Glu14Leu), one splice-region change (c.541-15T>G), and two frameshifts (p.Met73fs, p.Lys134fs). A representative allele is c.523A>C (p.Ser175Arg).

Functional studies demonstrate that the S175R mutant abolishes acyltransferase activity in COS-7 cells without altering secondary structure (PMID:11381255). A CRISPR/Cas9 Lrat–/– rat model recapitulates early-onset retinal degeneration with absent LRAT expression, progressive ERG loss, retinal thinning, and impaired vision (PMID:34281288). Biochemical analysis of the E14L variant reveals rapid proteasomal degradation and dysregulated retinoic acid homeostasis (PMID:28758396), and minigene assays confirm c.541-15T>G causes exon skipping (PMID:29973277).

A large sequencing screen of 82 North American LCA patients found no pathogenic LRAT variants, indicating that LRAT‐related LCA is rare in some populations (PMID:17438524).

Integration of genetic and experimental evidence supports a ClinGen moderate association between LRAT and LCA. Inclusion of LRAT in diagnostic gene panels enables precise molecular diagnosis, genetic counseling, and informs eligibility for emerging retinoid‐based therapies. Key take-home: Biallelic LRAT variants cause autosomal recessive LCA and should be considered in gene-based diagnostic pipelines.

References

• Nature Genetics • 2001 • Mutations in the gene encoding lecithin retinol acyltransferase are associated with early-onset severe retinal dystrophy. PMID:11381255
• Investigative Ophthalmology & Visual Science • 2012 • Early onset retinal dystrophy due to mutations in LRAT: molecular analysis and detailed phenotypic study. PMID:22570351
• Investigative Ophthalmology & Visual Science • 2007 • Identification of novel mutations in patients with Leber congenital amaurosis and juvenile RP by genome-wide homozygosity mapping with SNP microarrays. PMID:18055821
• International Journal of Molecular Sciences • 2021 • The Lrat-/- Rat: CRISPR/Cas9 Construction and Phenotyping of a New Animal Model for Retinitis Pigmentosa. PMID:34281288
• Biochemistry • 2017 • Impact of LCA-Associated E14L LRAT Mutation on Protein Stability and Retinoid Homeostasis. PMID:28758396
• Human Genomics • 2018 • A novel LRAT mutation affecting splicing in a family with early onset retinitis pigmentosa. PMID:29973277
• Molecular Vision • 2007 • Low prevalence of lecithin retinol acyltransferase mutations in patients with Leber congenital amaurosis and autosomal recessive retinitis pigmentosa. PMID:17438524

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