LIPF – Wolman Disease

LIPF, which encodes a key lipase involved in intracellular lipid catabolism, has been robustly implicated in Wolman disease, a fatal autosomal recessive lysosomal storage disorder. Multiple independent studies have identified deleterious mutations in LIPF that cause nearly complete loss of enzyme function, a finding that is critical for diagnostic decision‑making (PMID:9925650). This association is particularly evident in cases with early‐infantile onset where biochemical assays confirm absent or severely diminished lipase activity.

In one pivotal study, one patient was found to be compound heterozygous for two deletions leading to premature protein truncation, while another patient was homozygous for a missense mutation that replaces glycine with tryptophan, predicted to abrogate enzyme function (PMID:9925650). The selected variant, c.1064G>T (p.Gly321Trp), exemplifies the molecular mechanism underpinning the disease and adheres to criteria for a coding change, with full HGVS nomenclature and three‑letter amino acid codes.

Genetic evidence supports an autosomal recessive inheritance pattern for Wolman disease, with the disease manifesting only when both alleles of LIPF harbor pathogenic variants. Although detailed segregation analysis in extended families is not extensively reported, the de novo occurrence of biallelic loss‑of‑function variants in unrelated probands strengthens the association (PMID:10627498). Collectively, the observation of similar pathogenic variants across diverse populations further consolidates the gene–disease relationship.

The genetic spectrum includes both loss‑of‑function frameshift deletions and missense mutations that result in complete or near‑complete deficiency of lipase activity. These findings are bolstered by evidence from multiple case series showing that even compound heterozygosity for Wolman‐causing mutations is frequent among patients with related lipid storage disorders (PMID:10627498). The clear genotype–phenotype correlation observed across studies affirms the role of LIPF in disease pathology.

Functional studies have provided additional support by demonstrating that mutant LIPF proteins exhibit drastic reductions in enzymatic activity. In vitro experiments, including expression assays in fibroblasts and transfection models, have shown that mutations such as c.1064G>T (p.Gly321Trp) lead to a loss of protein stability and function, with enzyme activities reduced by over 99% (PMID:8695668; PMID:10562460). These results are consistent with the clinical presentation of Wolman disease, in which minimal residual lipase activity is insufficient to maintain normal lipid homeostasis.

No significant conflicting evidence has emerged to dispute the pathogenicity of LIPF variants in the context of Wolman disease. Although a degree of genetic heterogeneity exists between Wolman disease and related conditions such as cholesteryl ester storage disease, the biochemical and functional data specifically delineate the severe loss‐of‑function mutations leading to the Wolman phenotype. This clear demarcation is vital for selecting appropriate clinical management and genetic counseling strategies.

In summary, the collective genetic and functional evidence robustly supports a strong association between LIPF (HGNC:6622) and Wolman disease (MONDO_0019148). With a clear autosomal recessive inheritance pattern and multiple independent reports of pathogenic variants—including the representative c.1064G>T (p.Gly321Trp) mutation—the clinical utility of testing LIPF in suspected cases of Wolman disease is substantial. Key take‑home message: Accurate molecular diagnosis of Wolman disease via LIPF mutation analysis is critical for effective clinical decision‑making and patient management.

References

• Journal of lipid research • 1999 • Molecular defects underlying Wolman disease appear to be more heterogeneous than those resulting in cholesteryl ester storage disease PMID:9925650
• Journal of lipid research • 2000 • Compound heterozygosity for a Wolman mutation is frequent among patients with cholesteryl ester storage disease PMID:10627498
• Biochimica et biophysica acta • 1996 • Mutation of the catalytic site Asp177 to Glu177 in human pancreatic lipase produces an active lipase with increased sensitivity to proteases PMID:8695668
• 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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