Published online before print December 30, 2008

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(American Journal of Pathology. 2009;174:534-540.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080865

Co-Existent Pseudoxanthoma Elasticum and Vitamin K-Dependent Coagulation Factor Deficiency

Compound Heterozygosity for Mutations in the GGCX Gene

Qiaoli Li^*, Leon J. Schurgers, Ann C.M. Smith, Maria Tsokos, Jouni Uitto^* and Edward W. Cowen^¶

From the Department of Dermatology and Cutaneous Biology,^* Jefferson Medical College and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; the Cardiovascular Research Institute and VitaK, University of Maastricht, The Netherlands; the Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland; the Pediatric Tumor Biology and Ultrastructural Pathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and the Dermatology Branch,^¶ Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Pseudoxanthoma elasticum (PXE) is a multisystem disorder characterized by ectopic mineralization of connective tissues with primary manifestations in the skin, eyes, and cardiovascular system. The classic forms of PXE are due to mutations in the ABCC6 gene that encodes the ABCC6 protein, a putative transmembrane transporter expressed primarily in the liver and the kidneys. PXE-like clinical findings have been encountered in association with vitamin K-dependent coagulation factor deficiency, an autosomal recessive disorder that is due to mutations in either the GGCX or VKORC1 genes. In this study, we investigated a family with two siblings with characteristic features of PXE and vitamin K-dependent coagulation factor deficiency. Mutation analysis identified two GGCX mutations in the affected individuals (p. R83W and p.Q374X); however, no mutations in either ABCC6 or VKORC1 could be found. GGCX encodes a -glutamyl carboxylase necessary for activation of both coagulation factors in the liver and matrix gla protein, which, in fully carboxylated form, is able to prevent ectopic mineralization. Analysis of skin by specific antibodies demonstrated that matrix gla protein was found predominantly in undercarboxylated form and was associated with the mineralized areas in the patients’ lesional skin. These observations pathomechanistically suggest that, in our patients, reduced carboxylase activity results in a reduction of matrix gla protein carboxylation, thus allowing peripheral mineralization to occur. Our findings also confirm GGCX as the second gene locus causing PXE.

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