LCAT – LCAT deficiency

The lecithin cholesterol acyltransferase (LCAT) enzyme catalyzes the esterification of plasma cholesterol by transferring an acyl group from phosphatidylcholine to the 3-hydroxy group of cholesterol. Deficiency of this enzyme causes classic familial LCAT deficiency, an autosomal recessive syndrome marked by corneal opacities, hemolytic anemia, proteinuria/nephrotic syndrome, and low HDL levels (PMID:2370048). Biallelic loss-of-function variants in the LCAT gene lead to absent or severely reduced enzymatic activity, undetectable cholesterol esterification rate, and progressive renal failure.

Genetic evidence is robust: a report of 6 probands from 5 unrelated families identified homozygous or compound heterozygous missense, nonsense, and frameshift mutations with absent LCAT mass or activity in all patients (PMID:8432868). A systematic review described 215 cases (154 familial LCAT deficiency, 41 fish-eye disease, 20 unclassified) across 33 ethnic/racial groups, confirming autosomal recessive inheritance and consistent biochemical phenotype (PMID:34256778). Segregation in parents and unaffected heterozygous carriers further supports causality.

The variant spectrum includes over 27 missense variants, 10 nonsense/frameshift mutations, splice-site and intronic lesions. Representative changes include c.508T>C (p.Trp170Arg) in exon 4 (PMID:2370048) and c.951G>A (p.Met317Ile) in exon 6 (PMID:1859405). Recurrent alleles such as p.Thr147Ile have been identified in Dutch cohorts, accounting for 29% of referred low-HDL patients, with no single founder effect.

Segregation analyses confirm that homozygous or compound heterozygous individuals manifest classical LCAT deficiency, while heterozygotes show half-normal enzyme activity but no overt disease. A Japanese kindred demonstrated two affected siblings and enzyme‐deficient heterozygous offspring, consistent with autosomal recessive transmission (PMID:1859405).

Functional studies in COS-1 and HEK293 cells establish that multiple missense and truncating mutations disrupt LCAT secretion and abolish cholesterol esterification on HDL substrates (PMID:7721870). Frameshift insertions such as c.101dup (p.His35fs) lead to complete loss of enzyme production (PMID:1662503). Structural and glycosylation analyses pinpoint domains essential for lipid recognition and catalytic triad integrity.

Mechanistically, LCAT deficiency results from loss of function via protein misfolding, ER retention, and rapid degradation, or disruption of active‐site residues leading to haploinsufficiency. Rescue experiments with wild-type LCAT restore esterase activity, confirming direct genotype–phenotype correlation.

In conclusion, the association between LCAT and LCAT deficiency is Definitive. Autosomal recessive biallelic variants produce a consistent clinical and biochemical phenotype, enabling reliable genetic diagnosis, family screening, and targeted management of renal and cardiovascular complications.

References

• Human genetics • 1990 • Lecithin cholesterol acyl transferase deficiency: molecular analysis of a mutated allele. PMID:2370048
• Biochemical and biophysical research communications • 1991 • Lecithin-cholesterol acyltransferase deficiency with a missense mutation in exon 6 of the LCAT gene. PMID:1859405
• The Journal of clinical investigation • 1993 • Genetic and phenotypic heterogeneity in familial lecithin: cholesterol acyltransferase (LCAT) deficiency. PMID:8432868
• Lipids in health and disease • 2021 • LCAT deficiency: a systematic review with the clinical and genetic description of Mexican kindred. PMID:34256778
• The Journal of biological chemistry • 1995 • In vitro expression of structural defects in the lecithin-cholesterol acyltransferase gene. PMID:7721870
• Biochemical and biophysical research communications • 1991 • Molecular defect in familial lecithin:cholesterol acyltransferase (LCAT) deficiency: a single nucleotide insertion in LCAT gene causes a complete deficient type of the disease. PMID:1662503

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