The pathogenic c.1171A>G (p.Arg391Gly) and c.2359G>A (p.Val787Ile) ABCC6 variants display incomplete penetrance causing pseudoxanthoma elasticum in a subset of individuals.

Autor: Szeri F; Department of Dermatology and Cutaneous Biology, The Sidney Kimmel Medical College, and The PXE International Center of Excellence in Research and Clinical Care, Thomas Jefferson University, Pennsylvania, Philadelphia, USA.; Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary.; Department of Biochemistry, Semmelweis University, Budapest, Hungary., Miko A; MTA-SE Lendület Nephrogenetic Laboratory, Budapest, Hungary.; 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary., Navasiolava N; PXE Consultation Center, MAGEC Nord Reference Center for Rare Skin Diseases, Angers University Hospital, Angers, France., Kaposi A; MTA-SE Lendület Nephrogenetic Laboratory, Budapest, Hungary.; 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary.; Department of Programming Languages and Compilers, Eötvös Loránd University, Budapest, Hungary., Verschuere S; Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium., Molnar B; Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary., Li Q; Department of Dermatology and Cutaneous Biology, The Sidney Kimmel Medical College, and The PXE International Center of Excellence in Research and Clinical Care, Thomas Jefferson University, Pennsylvania, Philadelphia, USA., Terry SF; PXE International, District of Columbia, Washington, USA., Boraldi F; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy., Uitto J; Department of Dermatology and Cutaneous Biology, The Sidney Kimmel Medical College, and The PXE International Center of Excellence in Research and Clinical Care, Thomas Jefferson University, Pennsylvania, Philadelphia, USA., van de Wetering K; Department of Dermatology and Cutaneous Biology, The Sidney Kimmel Medical College, and The PXE International Center of Excellence in Research and Clinical Care, Thomas Jefferson University, Pennsylvania, Philadelphia, USA., Martin L; PXE Consultation Center, MAGEC Nord Reference Center for Rare Skin Diseases, Angers University Hospital, Angers, France., Quaglino D; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.; Interuniversity Consortium for Biotechnologies (CIB), Trieste, Italy., Vanakker OM; Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium., Tory K; MTA-SE Lendület Nephrogenetic Laboratory, Budapest, Hungary.; 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary., Aranyi T; Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary.; Department of Molecular Biology, Semmelweis University, Budapest, Hungary.
Jazyk: angličtina
Zdroj: Human mutation [Hum Mutat] 2022 Dec; Vol. 43 (12), pp. 1872-1881. Date of Electronic Publication: 2022 Nov 15.
DOI: 10.1002/humu.24498
Abstrakt: ABCC6 promotes ATP efflux from hepatocytes to bloodstream. ATP is metabolized to pyrophosphate, an inhibitor of ectopic calcification. Pathogenic variants of ABCC6 cause pseudoxanthoma elasticum, a highly variable recessive ectopic calcification disorder. Incomplete penetrance may initiate disease heterogeneity, hence symptoms may not, or differently manifest in carriers. Here, we investigated whether incomplete penetrance is a source of heterogeneity in pseudoxanthoma elasticum. By integrating clinical and genetic data of 589 patients, we created the largest European cohort. Based on allele frequency alterations, we identified two incomplete penetrant pathogenic variants, c.2359G>A (p.Val787Ile) and c.1171A>G (p.Arg391Gly), with 6.5% and 2% penetrance, respectively. However, when penetrant, the c.1171A>G (p.Arg391Gly) manifested a clinically unaltered severity. After applying in silico and in vitro characterization, we suggest that incomplete penetrant variants are only deleterious if a yet unknown interacting partner of ABCC6 is mutated simultaneously. The low penetrance of these variants should be contemplated in genetic counseling.
(© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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