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Functional Assessment of Missense Variants in the ABCC6 Gene Implicated in Pseudoxanthoma Elasticum, a Heritable Ectopic Mineralization Disorder

  • Author Footnotes
    4 These authors contributed equally to this work.
    Luke Kowal
    Footnotes
    4 These authors contributed equally to this work.
    Affiliations
    PXE International Center of Excellence in Research and Clinical Care, Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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  • Author Footnotes
    4 These authors contributed equally to this work.
    Jianhe Huang
    Footnotes
    4 These authors contributed equally to this work.
    Affiliations
    PXE International Center of Excellence in Research and Clinical Care, Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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  • Hongbin Luo
    Affiliations
    PXE International Center of Excellence in Research and Clinical Care, Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA

    Department of Dermatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
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  • Jagmohan Singh
    Affiliations
    Department of Pharmacology and Experimental Therapeutics, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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  • Adam E. Snook
    Affiliations
    Department of Pharmacology and Experimental Therapeutics, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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  • Jouni Uitto
    Affiliations
    PXE International Center of Excellence in Research and Clinical Care, Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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  • Qiaoli Li
    Correspondence
    Correspondence: Qiaoli Li, PXE International Center of Excellence in Research and Clinical Care, Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, 233 South 10th Street, Suite 431 BLSB, Philadelphia, Pennsylvania 19107, USA.
    Affiliations
    PXE International Center of Excellence in Research and Clinical Care, Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
    Search for articles by this author
  • Author Footnotes
    4 These authors contributed equally to this work.
Published:September 28, 2021DOI:https://doi.org/10.1016/j.jid.2021.08.435
      Pseudoxanthoma elasticum, a heritable multisystem ectopic mineralization disorder, is caused by inactivating mutations in the ABCC6 gene. The encoded protein, ABCC6, a transmembrane transporter, has a specialized efflux function in hepatocytes by contributing to plasma levels of inorganic pyrophosphate, a potent inhibitor of mineralization in soft connective tissues. Reduced plasma inorganic pyrophosphate levels underlie the ectopic mineralization in pseudoxanthoma elasticum. In this study, we characterized the pathogenicity of three human ABCC6 missense variants using an adenovirus-mediated liver-specific ABCC6 transgene expression system in an Abcc6–/– mouse model of pseudoxanthoma elasticum. Variants p.L420V and p.R1064W were found benign because they had abundance and plasma membrane localization in hepatocytes similar to the wild-type human ABCC6 transgene, normalized plasma inorganic pyrophosphate levels, and prevented mineralization in the dermal sheath of vibrissae in muzzle skin, a phenotypic hallmark in the Abcc6–/– mice. In contrast, p.S400F was shown to be pathogenic because it failed to normalize plasma inorganic pyrophosphate levels and had no effect on ectopic mineralization despite its normal expression and proper localization in hepatocytes. These results showed that adenovirus-mediated hepatic ABCC6 expression in Abcc6–/– mice can provide a model system to effectively elucidate the multifaceted functional consequences of human ABCC6 missense variants identified in patients with pseudoxanthoma elasticum.

      Abbreviations:

      ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology), ATP (adenosine triphosphate), CADD (Combined Annotation–Dependent Depletion), MAF (minor allele frequency), PPi (inorganic pyrophosphate), PXE (pseudoxanthoma elasticum), VUS (variant of unknown significance), WT (wild type)
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