Quantitative correlation of ENPP1 pathogenic variants with disease phenotype

Area of Science:

• Biochemistry
• Genetics
• Molecular Biology

Background:

• Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is a transmembrane glycoprotein regulating mineralization, bone formation, and immunity.
• ENPP1 deficiency causes diverse phenotypes, including arterial calcifications and hypopigmentation.

Purpose of the Study:

• To investigate the association between ENPP1 enzyme activity and clinical phenotypes.
• To correlate enzyme velocities of ENPP1 variants with disease severity and inheritance patterns.

Main Methods:

• Quantified enzyme velocities for 29 unique ENPP1 pathogenic variants in 41 patients and 33 literature variants.
• Utilized a high-throughput assay for triplicate catalytic velocity measurements.
• Correlated relative enzyme velocities with clinical diagnoses and disease severity.

Main Results:

• ENPP1 variants linked to autosomal dominant phenotypes reduced enzyme velocities by ≥50%.
• Insulin resistance-associated variants showed non-significant effects on enzyme velocity.
• In GACI, disease severity correlated with the most damaging ENPP1 variant in compound heterozygotes.

Conclusions:

• Enzyme velocities <50% of wild-type (WT) levels are likely associated with autosomal dominant ENPP1-related disorders.
• Disease severity in GACI infants is influenced by the most detrimental ENPP1 variant, not the mean velocity of all variants.