| Autor: |
Daniela Quaglino, Sharon F. Terry, Nastassia Navasiolava, Koen van de Wetering, Federica Boraldi, Ágnes Mikó, Qiaoli Li, Olivier Vanakker, Shana Verschuere, Tamas Aranyi, Flóra Szeri, Jouni Uitto, Ludovic Martin, Kálmán Tory, Ambrus Kaposi |
| Rok vydání: |
2020 |
| Předmět: |
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| DOI: |
10.1101/2020.11.26.20236489 |
| Popis: |
ABCC6 encodes a transmembrane transporter playing a primary role in the efflux of ATP from hepatocytes to the bloodstream. ATP is then cleaved to AMP and inorganic pyrophosphate, a major inhibitor of ectopic calcification. Pathogenic variants of ABCC6 cause pseudoxanthoma elasticum, a multisystemic recessive ectopic calcification disease of variable severity. One of the mechanisms influencing the heterogeneity of a disorder is the penetrance of pathogenic variants. The penetrance of a sequence variant shows the proportion of individuals developing the expected phenotype in the presence of the variant. Incomplete penetrance indicates that the disease does not develop in all the cases when the pathogenic variant is present. Here, we investigated whether incomplete penetrance participates in the heterogeneity of pseudoxanthoma elasticum. By integrating the clinical and genetic data of 590 patients, we created the largest European pseudoxanthoma elasticum cohort. We identified two incomplete penetrant pathogenic variants, p.(V787I) and p.(R391G), based on their allele frequencies in our cohort and in the European reference population of gnomAD. The detailed characterization of the frequent p.(R391G) pathogenic variant suggested only 2% penetrance with an unaltered severity of the clinical phenotype. Based on our biochemical analysis, we hypothesize that the variant becomes deleterious only if an interacting partner is mutated simultaneously. These data point to new molecular mechanisms by revealing the potential existence of the first interacting partner of ABCC6. Our data are important for genetic counseling of pseudoxanthoma elasticum, suggesting a much lower disease heritability of these pathogenic variants. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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