PXE Disease Origin Theories
There are currently two general hypotheses regarding the cause of PXE: the metabolic theory and the tissue-specific theory.
The metabolic theory is supported by the fact that 80% of people diagnosed with PXE exhibit a loss-of-function mutation in the ABCC6 gene which encodes the atypical, multi-drug associated, transmembrane transporter protein MRP6 (additional information available at http://www.ncbi.nlm.nih.gov/gene/368). This protein is normally expressed predominantly in the liver and kidney. The metabolic theory claims that the first step in the disease pathway is degradation and bioconjugation of a constituent of the extracellular matrix, specifically elastin. The theory further suggests that ABCC6 should remove this bio-conjugated metabolite but does not due to the mutation. Damage and remodeling of the extracellular matrix is then observed due to the elevated levels of this unidentified metabolite.
Kavukcuoglu NB, Li Q, Pleshko N, Uitto J. Connective tissue mineralization in Abcc6-/- mice, a model for pseudoxanthoma elasticum. Matrix Biol. 2012 May;31(4):246-52. Epub 2012 Mar 6. PubMed PMID: 22421595; PubMed Central PMCID: PMC3340454.
Jiang Q, Oldenburg R, Otsuru S, Grand-Pierre AE, Horwitz EM, Uitto J. Parabiotic heterogenetic pairing of Abcc6-/-/Rag1-/- mice and their wild-type counterparts halts ectopic mineralization in a murine model of pseudoxanthoma elasticum. Am J Pathol. 2010 Apr;176(4):1855-62. Epub 2010 Feb 25. PubMed PMID: 20185580; PubMed Central PMCID: PMC2843475.
Jiang Q, Endo M, Dibra F, Wang K, Uitto J. Pseudoxanthoma elasticum is a metabolic disease. J Invest Dermatol. 2009 Feb;129(2):348-54. Epub 2008 Aug 14. PubMed PMID: 18685618; PubMed Central PMCID: PMC3169309.
The tissue-specific theory is also supported by the fact that 80% of people diagnosed with PXE exhibit a loss-of-function mutation in the ABCC6 gene, transmembrane transporter protein MRP6 in multiple organ and tissue systems, including the liver. In contrast to the metabolic theory, the tissue-specific theory claims that disease manifestations in the multiple organ systems (e.g., ocular, cardio, vascular, and gastrointestinal) and the tissue-dependent loss of expression are associated with extracellular matrix damage observed. The theory further suggests that the ABCC6 loss of function at the local affected tissues is essential to the disease pathogenesis beyond the metabolic insult resulting from the loss of function in the liver.
Gheduzzi D, Boraldi F, Annovi G, DeVincenzi CP, Schurgers LJ, Vermeer C, Quaglino D, Ronchetti IP. Matrix Gla protein is involved in elastic fiber calcification in the dermis of pseudoxanthoma elasticum patients. Lab Invest. 2007 Oct;87(10):998-1008. Epub 2007 Aug 27. PubMed PMID: 17724449.
Boraldi F, Annovi G, Guerra D, Paolinelli Devincenzi C, Garcia-Fernandez MI, Panico F, De Santis G, Tiozzo R, Ronchetti I, Quaglino D. Fibroblast protein profile analysis highlights the role of oxidative stress and vitamin K recycling in the pathogenesis of pseudoxanthoma elasticum. Proteomics Clin Appl. 2009 Sep;3(9):1084-98. doi: 10.1002/prca.200900007. Epub 2009 Aug 26. PubMed PMID: 21137008.
Jiang Q, Li Q, Uitto J. Aberrant mineralization of connective tissues in a mouse model of pseudoxanthoma elasticum: systemic and local regulatory factors. J Invest Dermatol. 2007 Jun;127(6):1392-402. Epub 2007 Feb 1. PubMed PMID: 17273159.
SEPTEMBER 15, 2007
By Emilie Lamb, Research Assistant, PXE International
With Sharon Terry, Executive Director, PXE International
The original paper was published in the Journal of Medical Genetics, October 2007, pages 621-628.
This summary first appeared in the Fall 2007 PXE MemberGram.
PDF: Study on the Relationship between Genetic Mutations and Physical Symptoms of PXE
The lead researchers were Drs. Lionel Bercovitch, Jouni Uitto, Anne De Paepe, Denis Viljoen, Ellen Pfendner, Olivier Vanakker, and lay co-investigators Patrick Terry and Sharon Terry. Others who worked on the project and co-wrote the study were: Paul Coucke, Sara Fratta, Susan Hariri, Patricia McAndrew, Monica McClain, Anna-Susan Marais, Michele Ramsay, and Sophia Vourthis.
PXE is caused by changes, or mutations, in the ABCC6 gene that makes a protein involved in moving chemicals in and out of cells. The aim of this study was to identify the genotype (mutations in the ABCC6 gene) present in individuals with PXE and to determine if there is a relationship between the mutations and the phenotype. By identifying mutations that are common to PXE, early detection of the disease is easier. Understanding the relationship between the genotype and the phenotype might also allow healthcare providers to predict the severity of the disease.
The study used DNA from 270 individuals who had donated blood to the PXE International BioBank. These individuals were from North America, Europe, Australia, and South Africa. In addition, to donating blood for genetic studies, the participants answered questions about their family history and signs and symptoms of PXE. Overall, this study found 82 mutations, 39 of these had never been discovered before.
After all of this data was collected, the scientists tried to figure out how the mutation in the gene changed the protein. Some mutations make the protein stop working completely, meaning it can’t transport some substance out of the cell (the substance, called a substrate, is unknown). Other mutations damage the protein, but it still works somewhat. Some mutations have an unknown effect. After the scientists grouped the individuals based on how their protein was changed, they compared the phenotypes of the groups.
The phenotypes were coded according to the organs affected. To make this as simple as possible, an index was developed, called a Phenodex™ (see the Phenodex™ box). Creating the Phenodex™allowed the phenotype to be reduced to a few numbers. This made it easier to compare it to the genotype.
When these groups were compared, the scientists found no relationship between what mutations they had and their symptoms. This means that they could not look at one person who had mutation A and know that they would have symptom B, or to what degree they would have that symptom. It is not common to be able to predict the future course of a disease like PXE because the genotype is only part of the story – environment (lifestyle, diet, exercise…) accounts for a great deal in the course of a disease. We continue to study PXE, looking at the effects of both genetics and environment.