Trends in Molecular Medicine
OpinionMolecular genetics of pseudoxanthoma elasticum: a metabolic disorder at the environment–genome interface?
Section snippets
Clinical features of PXE
The clinical manifestations of PXE center on three major organ systems of the body (Table 1)2. First, the earliest manifestations are usually evident in the skin, and present as small yellowish dermal papules that tend to coalesce into larger plaques (Fig. 1). The affected skin becomes progressively lax, redundant and inelastic, causing an appearance of premature aging and eventually having considerable cosmetic impact. Histopathologic evaluation of skin depicts accumulation of pleiomorphic
Search for the PXE gene
Because the primary pathology of PXE resides in the elastic fibers, the genes involved in the synthesis and assembly of the elastic fiber network in the body were initially considered the prime candidate genes5. These include elastin on chromosome 7, elastin associated microfibrils, such as fibrillin 1 and fibrillin 2 on chromosomes 15 and 5, and lysyloxidase, a copper-dependent enzyme necessary for crosslinking of the elastic fibers, on chromosome 15. In addition, a number of other, recently
Implications for diagnosis of PXE
The studies of family B, as well as in a number of additional cases10., 11., 12., 13., 17., raise several intriguing questions regarding the genetics of PXE. The first issue relates to the mode of inheritance; traditionally, PXE has been reported to be inherited either in an autosomal recessive or autosomal dominant pattern, although a number of sporadic cases have also been noted. However, there is no molecular evidence of autosomal dominant inheritance in any of the families examined by us so
Future investigation
The critical next step towards understanding the pathology of PXE relates to the function of MRP6. As indicated above, this protein is primarily expressed in the liver and the kidney, and its function is currently unknown14., 15.. Its function as a transmembrane transporter protein is largely deduced from its sequence homology to MRP1. It is also conceivable that its function is modified by other members of the MRP family. This suggestion is based on the observation that mutations in another
Outstanding questions
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What is the physiological function of MRP6? Does it function as a transmembrane transporter of conjugated small molecules, similar to MRP1, the prototype of the MRP family of proteins?
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Is the activity of MRP6 modulated by the function of other members of the MRP family of transporters?
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What are the factors that might regulate the function of MRP6 or change its substrate specificity and/or flux?
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What are the mechanisms of calcification of elastic fibers in PXE? Do environmental, hormonal and/or
Acknowledgments
The original studies by the authors were supported by USPHS/NIH grant RO1 AR28450. The invaluable help of the patient advocacy organizations, PXE International and the National Association of PXE (NAPE), is acknowledged.
Glossary
- ABC transporters:
- A large protein superfamily responsible for transport of a wide variety of substrates including ions phospholipids steroids polysaccharides and peptides. This family includes the cystic fibrosis transmembrane conductance regulator (the cystic fibrosis gene); sulfonylurea receptors (SUR1 and 2); multidrug resistance proteins (MDR1 MDR2 and BSEP) homologs of P-glycoprotein; and the MRP family (MRP1–7) of proteins (see below).
- Angioid streaks:
- A characteristic ophthalmological
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