LIPF and Cholesteryl Ester Storage Disease

LIPF has been implicated in the pathogenesis of cholesteryl ester storage disease through well‐characterized autosomal recessive inheritance. Multiple independent studies have reported mutations in this gene in unrelated probands, underscoring a strong gene-disease association (PMID:10627498). The consistency of the inheritance pattern, combined with functional data, supports the clinical validity of this association for diagnostic decision-making and future research.

Genetic evidence for this disorder is bolstered by reports of compound heterozygosity and homozygosity for pathogenic variants in LIPF. In one seminal multi-patient study, genetic analysis of 15 unrelated CESD probands (PMID:10627498) revealed several distinct mutation types. A representative variant, for instance, is reported as c.1064G>T (p.Gly321Trp), which exemplifies the type of alteration leading to loss of function. Additional alleles include splice site and deletion mutations that disrupt the coding sequence and protein function.

Functional assessments further reinforce the pathogenicity of these genetic lesions. Experimental studies have demonstrated that mutant alleles lead to dramatically reduced enzyme activity, with HLAL activities measuring less than 2% of normal and virtually no detectable protein on immunoblot (PMID:10562460). These findings indicate that the molecular defect stems from a near-complete loss of lipase function, consistent with a loss-of-function mechanism.

No significant conflicting evidence has been reported regarding the association of LIPF with cholesteryl ester storage disease. Although mutations in LIPF have also been noted in the context of Wolman disease, the genetic and functional data specifically relating to CESD remain robust. The differences in phenotypic presentation between the two disorders are well understood within the framework of residual enzyme activity and molecular heterogeneity.

The integration of genetic and experimental data provides a coherent model: loss-of-function mutations in LIPF impair lysosomal lipase activity, leading to intracellular lipid accumulation and the clinical features of cholesteryl ester storage disease. This evidence, which spans segregation analysis, case series, and functional studies, offers a strong basis for utilizing LIPF variant testing in clinical diagnostics.

Key take‑home: Determining the presence of pathogenic LIPF variants, such as c.1064G>T (p.Gly321Trp), is critical for the accurate diagnosis and management of cholesteryl ester storage disease, ensuring informed genetic counseling and targeted therapy strategies.

References

• Journal of lipid research • 2000 • Compound heterozygosity for a Wolman mutation is frequent among patients with cholesteryl ester storage disease PMID:10627498
• Molecular genetics and metabolism • 1999 • Lysosomal acid lipase mutations that determine phenotype in Wolman and cholesterol ester storage disease PMID:10562460

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