1. Quantitative correlation of ENPP1 pathogenic variants with disease phenotype.
- Author
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Ansh AJ, Stabach PR, Ciccone C, Cao W, De La Cruz EM, Sabbagh Y, Carpenter TO, Ferreira CR, and Braddock DT
- Subjects
- Humans, Female, Genetic Variation, Male, Mutation genetics, Pyrophosphatases genetics, Phosphoric Diester Hydrolases genetics, Phosphoric Diester Hydrolases metabolism, Phenotype
- Abstract
Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) codes for a type 2 transmembrane glycoprotein which hydrolyzes extracellular phosphoanhydrides into bio-active molecules that regulate, inter alia, ectopic mineralization, bone formation, vascular endothelial proliferation, and the innate immune response. The clinical phenotypes produced by ENPP1 deficiency are disparate, ranging from life-threatening arterial calcifications to cutaneous hypopigmentation. To investigate associations between disease phenotype and enzyme activity we quantified the enzyme velocities of 29 unique ENPP1 pathogenic variants in 41 patients enrolled in an NIH study along with 33 other variants reported in literature. We correlated the relative enzyme velocities with the presenting clinical diagnoses, performing the catalytic velocity measurements simultaneously in triplicate using a high-throughput assay to reduce experimental variation. We found that ENPP1 variants associated with autosomal dominant phenotypes reduced enzyme velocities by 50 % or more, whereas variants associated with insulin resistance had non-significant effects on enzyme velocity. In Cole disease the catalytic velocities of ENPP1 variants associated with AD forms trended to lower values than those associated with autosomal recessive forms - 8-32 % vs. 33 % of WT, respectively. Additionally, ENPP1 variants leading to life-threatening vascular calcifications in GACI patients had widely variable enzyme activities, ranging from no significant differences compared to WT to the complete abolishment of enzyme velocity. Finally, disease severity in GACI did not correlate with the mean enzyme velocity of the variants present in affected compound heterozygotes but did correlate with the more severely damaging variant. In summary, correlation of ENPP1 enzyme velocity with disease phenotypes demonstrate that enzyme velocities below 50 % of WT levels are likely to occur in the context of autosomal dominant disease (due to a monoallelic variant), and that disease severity in GACI infants correlates with the more severely damaging ENPP1 variant in compound heterozygotes, not the mean velocity of the pathogenic variants present., Competing Interests: Declaration of competing interest DTB is an inventor on patents owned by Yale University for therapeutics treating ENPP1 deficiency and is an equity holder and receives research and consulting support from Inozyme Pharma, Inc. TOC is an advisor and has received consulting support from Inozyme Pharma. Y.S. is an employee of Inozyme Pharma., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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