LRAT – Severe Early-Childhood-Onset Retinal Dystrophy

Autosomal recessive LRAT deficiency presents in infancy with nyctalopia (HP:0000662), progressive visual field constriction (HP:0000612) and absent fundus autofluorescence. Seven unrelated patients with biallelic LRAT variants have been described: three individuals harboring c.523A>C (p.Ser175Arg) and a frameshift allele (PMID:11381255), and four patients with novel homozygous LRAT mutations identified by detailed sequencing (PMID:22570351). No formal segregation data have been reported.

Mechanistically, LRAT deficiency is due to loss of acyltransferase activity. The p.Ser175Arg mutant shows absent enzyme function in COS-7 cell assays (PMID:11381255), and biophysical studies confirm intact structure but abolished catalysis for this allele (PMID:21821024). A CRISPR/Cas9 Lrat-/- rat model recapitulates progressive retinal thinning, reduced ERG responses and vision deficits, mirroring the human phenotype (PMID:34281288).

Key take-home: Biallelic LRAT variants cause early-onset retinal dystrophy diagnosable by absent autofluorescence and enzymatic assays, guiding candidate selection for emerging retinoid-based therapies.

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
• Experimental eye research • 2011 • Lecithin retinol acyltransferase and its S175R mutant have a similar secondary structure content and maximum insertion pressure but different enzyme activities. PMID:21821024
• 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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