Pseudoxanthoma elasticum: molecular genetics and putative pathomechanisms.
Pseudoxanthoma elasticum (PXE), a prototypic heritable disorder with ectopic mineralization, manifests with characteristic skin findings, ocular involvement and cardiovascular problems, with considerable morbidity and mortality. The classic forms of PXE are due to loss-of-function mutations in the ABCC6 gene, which encodes ABCC6, a transmembrane efflux transporter expressed primarily in the liver. Several lines of evidence suggest that PXE is a primary metabolic disorder, which in the absence of ABCC6 transporter activity, displays reduced plasma anti-mineralization capacity due to reduced fetuin-A and matrix gla-protein (MGP) levels. MGP requires to be activated by gamma-glutamyl carboxylation, a vitamin K-dependent reaction, to serve in an anti-mineralization role in the peripheral connective tissue cells. Although the molecules transported from the hepatocytes to circulation by ABCC6 in vivo remain unidentified, it has been hypothesized that a critical vitamin K derivative, such as reduced vitamin K conjugated with glutathione, is secreted to circulation physiologically, but not in the absence of ABCC6 transporter activity. As a result, activation of MGP by gamma-glutamyl carboxylase is diminished, allowing slow yet progressive mineralization of connective tissues characteristic of PXE. Understanding of the pathomechanistic details of PXE provides a basis for the development of targeted molecular therapies for this currently intractable disease.
Uitto
Jouni
J
Department of Dermatology and Cutaneous Biology, Jefferson Medical College and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA. Jouni.uitto@jefferson.edu
Li
Qiaoli
Q
Jiang
Qiujie
Q
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D019735:Carbon-Carbon Ligases / Q000378:metabolism; D003238:Connective Tissue / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D011561:Pseudoxanthoma Elasticum / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D014812:Vitamin K / Q000378:metabolism; D060749:alpha-2-HS-Glycoprotein; D000097568:Matrix Gla Protein
D018528:ATP-Binding Cassette Transporters; D001798:Blood Proteins; D002135:Calcium-Binding Proteins; D019735:Carbon-Carbon Ligases; D016326:Extracellular Matrix Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014812:Vitamin K; D060749:alpha-2-HS-Glycoprotein; D000097568:Matrix Gla Protein; C102029:ABCC6 protein, human; C556354:AHSG protein, human; C504743:Abcc6 protein, mouse; C556357:Ahsg protein, mouse; C020660:glutamyl carboxylase