For the second time in seven years, PXE International convened a PXE research meeting. There have been many new discoveries in pseudoxanthoma elasticum research since the first meeting in 1997. The gene associated with PXE, ABCC6, was discovered, and important work on the characteristics of the protein and the cell was conducted. Also, a large epidemiological study was conducted, as were a number of smaller clinical studies.
Below you will find brief summaries of the presenations from this meeting. Click to expand or hide.
*Speakers who received support, either funding or biological samples, from PXE International are indicated with an asterisk after their names.
Translational Research for Rare Diseases: Using the Tools of the Trade
Francis Collins, MD, PhD, Director, National Human Genome Research Institute at NIH [biography not available]
Upon completion of the Human Genome Research project in 2003, an unprecedented amount of information about human genes was put into the public domain. One of the initiatives taken up by the NIH is increasing access to “chemical” libraries—libraries of small drug-like molecules, which will help to understand the pathways involved in diseases such as PXE. Through this initiative NIH may take a more active role in developing therapies in areas of less interest to the private sector, for instance, in the realm of rare diseases. Identifying the small molecules involved in PXE is a key early step in creating treatments for PXE or ways to prevent its effects over time.
Decoding the Human Genome by Multi-Species Sequence Comparison
Eric Green*, MD, PhD, Scientific Director, National Human Genome Research Institute [biography not available]
The NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program makes detailed comparisons between similar genomic regions and genes among multiple different species. These comparisons allow researchers to determine the parts of the genes and regions that have been preserved during evolution, shedding light on the “functionally important elements” of the genome. Having the PXE gene in this program provides great opportunity to get detailed information about how this gene works and how changes in the gene can cause PXE. This kind of information forms a crucial foundation for safe and effective approaches to treatment. This work is being conducted by Timothy Hefferon, in Dr. Green´s lab, in collaboration with PXE International.
ATP-Binding Cassette Transporters and Human Disease
Michael Dean*, PhD, Chief of the Human Genetics Section, Laboratory of Genomic Diversity, National Cancer Institute, NIH
Dr. Dean reported that genes in the same family as the gene for PXE (ABCC6) pump compounds in and out of cells. However, it is not yet known if other genes in this family work together with the PXE gene or if one or another compensates for a lack of function in ABCC6. Discovering what and how compounds are pumped will be just as important as the day the gene was discovered. Dr. Dean is working with PXE International to understand the gender skew in PXE, the possibility that urine from affected individuals may offer a clue as to the function of the gene and the problem the defect causes.
Pairing ABC Transporters with Substrates: Correlation of ABC-Transporter Expression with Chemosensitivity in the NC160 Cell Panel
Michael Gottesman*, MD, Deputy Director for Intramural Research, NIH, and Chief of the Laboratory of Cell Biology at National Cancer Institute, NIH
The National Cancer Institute Developmental Therapeutics Program works with human cells grown in a laboratory setting to see how they react in response to potential medications for anti-cancer activity. Dr. Gottesman discovered that the presence of ABC transporters reduced the effect of such drugs used during chemotherapy. Even though these types of drugs are not being considered for PXE treatment, watching the way these drugs interact with ABC transporters can help us better understand the kinds of compounds that are recognized by the transporters, which can lead to the developments of PXE treatments down the road.
Substrate Selectivity of New MRP Family Members
Gary Kruh, MD, PhD, Medical Science Division, Fox Chase Medical Center, PA [biography not available]
Dr. Kruh´s team examined the transporter activity of a protein related to the one produced by the PXE gene. Understanding the specific activities of a related protein can help us understand how the protein involved in PXE works, or help us design better studies on the activities of this protein. This is part of the basic research needed for forming the foundation of a PXE treatment.
Metabolic Disorders of the Liver and Kidney
David Perlmutter, MD, Professor and Chair of the Department of Pediatrics, Professor of Cell Biology and Physiology at the University of Pittsburg School of Medicine, Physician-in-Chief and Scientific Director of Children´s Hospital of Pittsburgh, PA [biography not available]
Dr. Perlmutter conducts research on a genetic disorder called Alpha-1 antitrypsin deficiency in which toxic substances build up in the cells of the liver and lungs, causing severe damage. Since the gene associated with PXE is mostly expressed in the liver and kidney, it is possible that mutations in the PXE gene also cause a buildup of substances in the cell. Therefore, understanding more about the disorder Dr. Perlmutter studies may help researchers understand PXE better or devise better studies for PXE.
ABCC6 Gene Mutations in South African Patients with PXE
Michele Ramsay*, PhD, Professor in Human Genetics at the National Health Laboratory Service and University of the Witwatersrand, Johannesburg, South Africa
Dr. Ramsay discussed results of mutation analysis in the PXE population in South Africa. Dr. Ramsay´s team found some familiar mutations and several potential new mutations. This research gives us a more complete “library” of which mutations are related to PXE, and will help to develop accurate genetic tests.
Autosomal Dominant Inheritance in PXE: Debunking the Myth
Franziska Ringpfeil*, MD, Assistant Professor, Department of Dermatology at Thomas Jefferson University, Philadelphia, PA [biography not available]
Dr. Ringpfeil´s study looked at the DNA of several families in which PXE appeared to be inherited as a result of a mutation of only one gene, instead of both genes. This is called dominant inheritance. The results of the study failed to show that PXE arises from a single mutation, but rather two mutations, one on each gene, are necessary for PXE. This study provided evidence to support genetic counseling about PXE and makes it easier to give families with PXE accurate information.
Standardization of a Mutation Detection Strategy for ABCC6
Ellen Pfendner*, PhD, Assistant Professor at Thomas Jefferson University, and Manager of the Molecular Diagnostic Services, Philadelphia, PA
Dr. Pfendner and her research group are creating a method to identify mutations in the PXE gene. Understanding how to find the most common mutations has led to the development of a sample genetic test for PXE. This research has resulted in the identification of new mutations not previously described, and has laid the groundwork for future testing. This project was initiated and partially funded by PXE International.
Analysis of ABCC6/MRP6 Gene Expression in Human Cell Lines
Tamás Arányi*, PhD, Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary
Dr. Arányi has studied the PXE gene to learn more about how it turns on and off in cells by looking at the activity of similar genes. Minor differences between the PXE gene and similar genes can teach us how the disease-causing PXE gene is itself turned on and off. This also helps to carefully explain exactly what the mutations for PXE are doing in the cell, and how they are doing it. This work is being done in Dr. Váradi´s research group.
Localization and Biophysiology: Analysis of Missense PXE – Mutants of ABCC6
András Váradi, PhD, Laboratory of Active Transport Proteins, Institute of Enzymology, Hungarian Academy of Sciences in Budapest, Hungary
Dr. Váradi's group looked at the transport activity of products of the PXE gene, ABCC6. The research group identified three mutations of the PXE gene that prevents the transport activity. By identifying the mechanisms that break down in people with PXE, treatments that restore function or make up for the breakdown in other ways can potentially be developed.
How Fibroblasts Could Be Involved in the Pathogenesis of PXE
Ivonne Ronchetti, PhD, Chair or Pathology in the Department of Biomedical Sciences, School of Medicine at the University of Modena and Reggio Emilia, Italy
Dr. Ronchetti´s group looked at a specific type of cell called fibroblasts. They discovered that these cells behave and look differently in people with PXE compared to people who are not affected by PXE. This group studied the behavior of fibroblast cells to determine how PXE affects them. Research from this group provides useful information about the specific activities, or lack of them that occur because of the mutations in the gene associated with PXE.
The Pathobiology of Acquired Pseudoxanthoma Elasticum
Olivier Le Saux, PhD, Assistant Professor in the Department of Cell and Molecular Biology at the John A. Burns School of Medicine, University of Hawaii at Manoa, Hawaii
Dr. Le Saux investigated how people with another genetic disorder, beta thalessemia, develop symptoms nearly identical to those of PXE, and how some of the biological changes appear to be similar. This group used a mouse model to study the effects of beta thalessemia and discovered reduced expression of the PXE gene and calcium deposits occurred in some of the tissues. Even though these disorders are not directly related, the presence of PXE-like symptoms in a mouse with beta-thalessemia provides an additional model for how these symptoms come about and suggests ideas for future treatment for PXE.
Stargardt Disease, Retinitis Pigmentosa, and Age-Related Macular Degeneration
Richard Alan Lewis, MD, MS, Professor of Ophthalmology, Pediatrics, Medicine, and Molecular Genetics and Faculty Associate at the Huffington Center on Aging, Baylor College of Medicine, Houston, Texas [biography not available]
Dr. Lewis discussed three disorders, Stargardt disease, retinitis pigmentosa, and age- related macular degeneration. All of these disorders result in some loss of central vision, and are caused by or linked with a single gene in the same family as the gene responsible for PXE. The information from this research group may lead PXE researchers directly to discoveries about PXE and its gene that may provide useful information for other human disorders beyond PXE.
CFTR: Phenotypes, Genotypes, and Functions
John Mickle, PhD, Assistant Professor in the Department of Pediatrics and the McKuisck-Nathans Institute of Medical Genetics at Johns Hopkins School of Medicine, Baltimore, MD [biography not available]
Dr. Mickle discussed the genetic disorder, cystic fibrosis (CF), and how different mutations result in different outcomes in people affected by the disorder. Over 1,300 mutations have been identified in the gene responsible for CF, but not all mutations have the same effect. By classifying mutations into groups resulting in similar affects, therapeutic interventions can be more efficient and targeted for a large group of mutations. The cystic fibrosis experience shows how certain phenotypes correlate with specific genotypes, and how understanding the effect of CF mutations provides a basis for the development of applicable gene-based therapies.
Liver-Related ABC Transporter Diseases Related to Inheritable Defect in Bile Secretion and Cholestasis
Irwin Arias*, MD, Tufts University School of Medicine, and NIH
Dr. Arias discussed several genetic disorders that result from mutations in genes in the same family as ABCC6, the PXE gene. He also discussed the different ways new information was discovered on these disorders. Studying other members of the family to which ABCC6 belongs can help speed discoveries about ABCC6 as well as demonstrate different ways these discoveries are made.
ABCA1: Identification of the Genetic Defect in Tangier Disease and Its Role in Reverse-Cholesterol Transport and Atherosclerosis
H. Bryan Brewer, Chief, Molecular Disease Branch, National Heart, Lung and Blood Institute, NIH [biography not available]
Dr. Brewer described another disorder arising from a gene in the same family as the PXE gene, tangier disease. This genetic disorder is associated with premature cardiovascular disease. Studying related disorders can lead to insight into PXE and lead to treatments, or suggest useful lines of investigation for PXE.
A Mouse Model for Pseudoxanthoma Elasticum: Targeted Ablation for ABCC6 Results in Aberrant Calcification of Connective Tissue
Jouni Uitto*, MD, PhD, Professor and Chair, Department of Dermatology and Cutaneous Biology, and Professor of Biochemistry and Molecular Pharmacology, Jefferson Medical College, Philadelphia, PA
Dr. Uitto´s group used techniques to produce a mouse that does not have the PXE gene and is therefore expected to have PXE. This mouse is then used to study the symptoms of PXE, such as the development of calcifications in the skin, blood vessels, and eyes. Availability of a mouse model provides a consistent model of PXE that is easily relatable to the human counterpart of this condition. In addition, this research allows us to use the mice models for treatment trials in the near future.
Visceral Calcifications As Part of the Phenotype of PXE: Ultrasonographical Findings in Belgian Patients and Heterozygous Carriers
Olivier Vanakker*, MD, PhD Candidate, Center for Medical Genetics of the Ghent University Hospital, Ghent, Belgium
Dr. Vanakker examined individuals with PXE and carriers of the PXE gene by using ultrasound. All individuals were examined for calcification in tissues of the abdominal organs, and were tested for kidney and liver function, and calcium levels. Abdominal calcification was found in most of the individuals with PXE and in some of the carriers. These calcifications did not seem to influence organ function. This research helps to establish the link between calcification in various body tissues and PXE. Dr. Vanakker is a member of the Ghent PXE research group in Professor Anne De Paepe´s group.
Mineral Deposition in Pseudoxanthoma Elasticum: Regulation by Cell and Matrix Factors
Irving M. Shapiro, BDS, PhD, Professor of Orthopaedic Surgery and Director of the Tissue Engineering and Regenerative Medicine Graduate Training Program at Thomas Jefferson University, Philadelphia, PA [biography not available]
Dr. Shapiro gave an overview of the way minerals are deposited in different skeletal tissues of the body, and discussed some of the factors involved in the process of formation of a normal hard tissue. Abnormal deposition of minerals is a complication many individuals with PXE must face. The more that is known about the interaction involved, the better we can develop ways to control those processes that result in development of PXE.
Genotype-Phenotype Correlations
Patrick Terry*, JAD (Just a Dad), Founding President, PXE International, Washington DC
PXE International assembled a detailed database of the mutations that cause PXE and the clinical features of individuals with PXE. Analysis of the data reveals no association between specific mutations and specific symptoms. The fact that there is no association suggests the importance of continuing to gather as much genetic information and clinical information as possible to make the data more complete.
Pregnancy and Obstetrical Outcomes in PXE
Lionel Bercovitch*, MD, Clinical Professor of Dermatology at the Brown Medical School, Providence, RI and Founding Medical Director of PXE International
Dr. Bercovitch and his research group analyzed information about pregnancy and reproductive outcomes obtained from a group of pregnant women with PXE. Results show that the ultimate course of PXE in women appears unaffected by single or multiple pregnancies. This data also provides women with PXE and health care providers with information that reassures them pregnancy is not more hazardous for those with PXE than in the unaffected population, and that PXE does not adversely affect the fetus.
Download "Pregnancy and Obstetrical Outcomes in PXE" from British Journal of Dermatology
Treatments for Eye Manifestations of PXE
Wayne Fuchs, MD, Clinical Professor of Ophthalmology at the Mount Sinai School of Medicine, New York, NY
Dr. Fuchs reviewed how PXE affects the eye and the current treatments for ophthalmologic complications of this disease. He also discussed available strategies to reduce the impact of eye complications on the quality of life of those with PXE.
Preliminary Epidemiological Study Results
Sharon F. Terry*, MA, Founding Executive Director, PXE International, Washington DC
An epidemiological study that consisted of questions about nearly every organ system, quality of life, diet, and reproductive experience was conducted in order to obtain a complete picture of the signs and symptoms associated with PXE. Over 600 individuals completed a 46-page questionnaire with over 900 fields. The Centers for Disease Control and Prevention helped to analyze the data. Information from this study helps to characterize the PXE population and give a better picture of the disease and its progression.
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