Research Progress in Pseudoxanthoma Elasticum and Related Ectopic Mineralization Disorders

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Abstract

Heritable ectopic mineralization disorders represent a phenotypically diverse group of conditions characterized by deposition of calcium phosphate complexes in soft connective tissues. The prototype of such conditions is pseudoxanthoma elasticum (PXE), and related conditions with overlapping clinical features include generalized arterial calcification of infancy (GACI) and arterial calcification due to CD73 deficiency (ACDC). Molecular genetic investigations have revealed mutations in the genes physiologically involved in generation of inorganic pyrophosphate (PPi) and phosphate (Pi), and the findings suggest a unifying pathomechanism relating to reduced PPi/Pi ratio. This hypothesis is based on the notion that PPi serves as a powerful inhibitor of mineralization while Pi is a pro-mineralization factor, and an appropriate PPi/Pi ratio is critical for prevention of ectopic mineralization under homeostatic conditions.

PXE International, the premiere patient support organization, advocating on behalf of patients and families with PXE, sponsors regular research meetings evaluating the progress in this and related ectopic mineralization disorders. The latest meetings were held in September 2014 in Bethesda, MD and in September 2015 in Budapest, Hungary. This report summarizes the latest progress in research on PXE and related ectopic mineralization disorders, based on presentations and discussions in these meetings, with pharmacologic implications for currently intractable disorders.

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Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients.

Matthew Budoff, Leslee J Shaw, Sandy Liu … (2007)

The purpose of this study was to develop risk-adjusted multivariable models that include risk factors and coronary artery calcium (CAC) scores measured with electron-beam tomography in asymptomatic patients for the prediction of all-cause mortality. Several smaller studies have documented the efficacy of CAC testing for assessment of cardiovascular risk. Larger studies with longer follow-up will lend strength to the hypothesis that CAC testing will improve outcomes, cost-effectiveness, and safety of primary prevention efforts. We used an observational outcome study of a cohort of 25,253 consecutive, asymptomatic individuals referred by their primary physician for CAC scanning to assess cardiovascular risk. Multivariable Cox proportional hazards models were developed to predict all-cause mortality. Risk-adjusted models incorporated traditional risk factors for coronary disease and CAC scores. The frequency of CAC scores was 44%, 14%, 20%, 13%, 6%, and 4% for scores of 0, 1 to 10, 11 to 100, 101 to 400, 401 to 1,000, and >1,000, respectively. During a mean follow-up of 6.8 +/- 3 years, the death rate was 2% (510 deaths). The CAC was an independent predictor of mortality in a multivariable model controlling for age, gender, ethnicity, and cardiac risk factors (model chi-square = 2,017, p 1,000, respectively (p 1,000 (p < 0.0001). This large observational data series shows that CAC provides independent incremental information in addition to traditional risk factors in the prediction of all-cause mortality.

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NT5E mutations and arterial calcifications.

Cynthia St. Hilaire, Shira G Ziegler, Thomas Markello … (2011)

Arterial calcifications are associated with increased cardiovascular risk, but the genetic basis of this association is unclear. We performed clinical, radiographic, and genetic studies in three families with symptomatic arterial calcifications. Single-nucleotide-polymorphism analysis, targeted gene sequencing, quantitative polymerase-chain-reaction assays, Western blotting, enzyme measurements, transduction rescue experiments, and in vitro calcification assays were performed. We identified nine persons with calcifications of the lower-extremity arteries and hand and foot joint capsules: all five siblings in one family, three siblings in another, and one patient in a third family. Serum calcium, phosphate, and vitamin D levels were normal. Affected members of Family 1 shared a single 22.4-Mb region of homozygosity on chromosome 6 and had a homozygous nonsense mutation (c.662C→A, p.S221X) in NT5E, encoding CD73, which converts AMP to adenosine. Affected members of Family 2 had a homozygous missense mutation (c.1073G→A, p.C358Y) in NT5E. The proband of Family 3 was a compound heterozygote for c.662C→A and c.1609dupA (p.V537fsX7). All mutations found in the three families result in nonfunctional CD73. Cultured fibroblasts from affected members of Family 1 showed markedly reduced expression of NT5E messenger RNA, CD73 protein, and enzyme activity, as well as increased alkaline phosphatase levels and accumulated calcium phosphate crystals. Genetic rescue experiments normalized the CD73 and alkaline phosphatase activity in patients' cells, and adenosine treatment reduced the levels of alkaline phosphatase and calcification. We identified mutations in NT5E in members of three families with symptomatic arterial and joint calcifications. This gene encodes CD73, which converts AMP to adenosine, supporting a role for this metabolic pathway in inhibiting ectopic tissue calcification. (Funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute of the National Institutes of Health.).

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ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report.

Robert Jansen, Suzanne Duijst, Sunny Mahakena … (2014)

Mutations in ABCC6 underlie the ectopic mineralization disorder pseudoxanthoma elasticum (PXE) and some forms of generalized arterial calcification of infancy, both of which affect the cardiovascular system. Using cultured cells, we recently showed that ATP-binding cassette subfamily C member 6 (ABCC6) mediates the cellular release of ATP, which is extracellularly rapidly converted into AMP and the mineralization inhibitor inorganic pyrophosphate (PPi). The current study was performed to determine which tissues release ATP in an ABCC6-dependent manner in vivo, where released ATP is converted into AMP and PPi, and whether human PXE ptients have low plasma PPi concentrations. Using cultured primary hepatocytes and in vivo liver perfusion experiments, we found that ABCC6 mediates the direct, sinusoidal, release of ATP from the liver. Outside hepatocytes, but still within the liver vasculature, released ATP is converted into AMP and PPi. The absence of functional ABCC6 in patients with PXE leads to strongly reduced plasma PPi concentrations. Hepatic ABCC6-mediated ATP release is the main source of circulating PPi, revealing an unanticipated role of the liver in systemic PPi homeostasis. Patients with PXE have a strongly reduced plasma PPi level, explaining their mineralization disorder. Our results indicate that systemic PPi is relatively stable and that PXE, generalized arterial calcification of infancy, and other ectopic mineralization disorders could be treated with PPi supplementation therapy. © 2014 American Heart Association, Inc.

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Author and article information

Journal

Journal ID (nlm-journal-id): 0426720

Journal ID (pubmed-jr-id): 4839

Journal ID (nlm-ta): J Invest Dermatol

Journal ID (iso-abbrev): J. Invest. Dermatol.

Title: The Journal of investigative dermatology

ISSN (Print): 0022-202X

ISSN (Electronic): 1523-1747

Publication date Nihms-submitted: 17 November 2015

Publication date (Print): March 2016

Publication date PMC-release: 01 September 2016

Volume: 136

Issue: 3

Pages: 550-556

Affiliations

[1 ]Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA

[2 ]Institute of Enzymology, Hungarian Academy of Science, Budapest, Hungary

[3 ]PXE International, Washington, DC, USA

Author notes

Address for Correspondence: Jouni Uitto, MD, PhD, Department of Dermatology and Cutaneous Biology, The Sidney Kimmel Medical College at Thomas Jefferson University, 233 S. 10 ^th Street, Suite 450 BLSB, Philadelphia, PA 19107, Tel: 215-503-5785, Fax: 215-503-5788, Jouni.Uitto@ 123456jefferson.edu

Article

Manuscript ID: NIHMS734148

DOI: 10.1016/j.jid.2015.10.065

PMC ID: 4765001

PubMed ID: 26902123

SO-VID: eeee1275-f52f-4ae4-a834-9e7b0bc11d30

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Research Progress in Pseudoxanthoma Elasticum and Related Ectopic Mineralization Disorders

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Karger: Dermatology

Most cited references 65

Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients.

NT5E mutations and arterial calcifications.

ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report.

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