LRAT – Retinitis Pigmentosa

Retinitis pigmentosa is a genetically heterogeneous inherited retinal dystrophy characterized by progressive photoreceptor degeneration and nyctalopia. LRAT encodes lecithin retinol acyltransferase, essential for retinoid cycling in the retinal pigment epithelium (LRAT, Retinitis Pigmentosa). Biallelic LRAT variants have been implicated in early-onset autosomal recessive retinitis pigmentosa.

The genetic landscape includes a homozygous intronic splice variant c.541-15T>G causing exon skipping in a consanguineous Pakistani family with ARRP (LOD 5.40) (PMID:29973277). A separate homozygous deletion c.217_218delAT (p.Met73AspfsTer?) was identified in a 2.5-year-old patient with nyctalopia and an RPE65-like phenotype (PMID:17011878). Screening of 267 retinal dystrophy patients revealed missense and frameshift mutations including c.523A>C (p.Ser175Arg) and c.400_401del (p.Lys134fs) in three additional cases (PMID:11381255). APEX-based microarray analysis identified four more patients with homozygous LRAT mutations in early-onset retinal dystrophy (PMID:22570351).

Variants span intronic cryptic acceptor, frameshift, splice and catalytic domain missense changes. Reported alleles include c.541-15T>G, c.217_218delAT (p.Met73AspfsTer?), c.400_401del (p.Lys134fs) and c.523A>C (p.Ser175Arg). All follow an autosomal recessive inheritance.

Segregation analysis confirmed co-segregation of c.541-15T>G with disease in multiple affected family members (affected_relatives=2). Homozygous carriers uniformly present early-onset nyctalopia and progressive visual field constriction.

Functional studies demonstrate that p.Ser175Arg abolishes LRAT acyltransferase activity in COS-7 cells (PMID:11381255). Minigene assays of c.541-15T>G confirm weakening of the authentic acceptor site and exon skipping (PMID:29973277). The E14L (p.Glu14Leu) mutation causes accelerated proteasomal degradation and altered retinoid homeostasis (PMID:28758396). A CRISPR/Cas9 Lrat-/- rat model exhibits reduced ERG amplitudes and retinal thinning, recapitulating the human dystrophy phenotype (PMID:34281288).

Collectively, biallelic LRAT variants disrupt vitamin A metabolism in the retinal pigment epithelium, leading to photoreceptor dysfunction and retinitis pigmentosa. Early genetic diagnosis enables patient stratification for retinoid replacement and emerging gene therapies.

References

• Human genomics | 2018 | A novel LRAT mutation affecting splicing in a family with early onset retinitis pigmentosa. PMID:29973277
• American journal of ophthalmology | 2006 | Screening genes of the retinoid metabolism: novel LRAT mutation in leber congenital amaurosis. PMID:17011878
• 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
• Biochemistry | 2017 | Impact of LCA-Associated E14L LRAT Mutation on Protein Stability and Retinoid Homeostasis. PMID:28758396
• International journal of molecular sciences | 2021 | The Lrat-/- Rat: CRISPR/Cas9 Construction and Phenotyping of a New Animal Model for Retinitis Pigmentosa. PMID:34281288

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