Co-Existent Pseudoxanthoma Elasticum and Vitamin K-Dependent Coagulation Factor Deficiency: Compound Heterozygosity for Mutations in the GGCX Gene

• Published in: The American journal of pathology Vol. 174; no. 2; pp. 534 - 540
• Main Authors: Li, Qiaoli, Schurgers, Leon J, Smith, Ann C.M, Tsokos, Maria, Uitto, Jouni, Cowen, Edward W
• Format: Journal Article
• Language: English
• Published: Bethesda, MD ASIP 01-02-2009; American Society for Investigative Pathology
• Subjects: Amino Acid Sequence; Base Sequence; Biological and medical sciences; Blood Coagulation Factors; Carbon-Carbon Ligases; Coagulation Protein Disorders - complications; Coagulation Protein Disorders - genetics; DNA Mutational Analysis; Female; Heterozygote; Humans; Immunohistochemistry; Investigative techniques, diagnostic techniques (general aspects); Male; Medical sciences; Microscopy, Electron, Transmission; Middle Aged; Mixed Function Oxygenases - genetics; Molecular Sequence Data; Multidrug Resistance-Associated Proteins - genetics; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Pedigree; Polymerase Chain Reaction; Pseudoxanthoma Elasticum - complications; Pseudoxanthoma Elasticum - genetics; Pseudoxanthoma Elasticum - pathology; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Sequence Homology, Amino Acid; Vitamin K; Vitamin K Epoxide Reductases; Skin disease; Elastic tissue disease; Nutrition disorder; Vitamin deficiency; Hemopathy; Genetic disease; Compound heterozygosity; Metabolic disorder; Anatomic pathology; Gene; Genetics; Pseudoxanthoma elasticum; Mutation; Malnutrition; Coagulopathy; Nutritional status; Coagulation factor deficiency; Vitamin K
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2009.080865

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 gamma-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.