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Generalized Arterial Calcification of Infancy and Pseudoxanthoma Elasticum Can Be Caused by Mutations in Either ENPP1 or ABCC6  Yvonne Nitschke, Geneviève.

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Presentation on theme: "Generalized Arterial Calcification of Infancy and Pseudoxanthoma Elasticum Can Be Caused by Mutations in Either ENPP1 or ABCC6  Yvonne Nitschke, Geneviève."— Presentation transcript:

1 Generalized Arterial Calcification of Infancy and Pseudoxanthoma Elasticum Can Be Caused by Mutations in Either ENPP1 or ABCC6  Yvonne Nitschke, Geneviève Baujat, Ulrike Botschen, Tanja Wittkampf, Marcel du Moulin, Jacqueline Stella, Martine Le Merrer, Geneviève Guest, Karen Lambot, Marie-Frederique Tazarourte-Pinturier, Nicolas Chassaing, Olivier Roche, Ilse Feenstra, Karen Loechner, Charu Deshpande, Samuel J. Garber, Rashmi Chikarmane, Beat Steinmann, Tatevik Shahinyan, Loreto Martorell, Justin Davies, Wendy E. Smith, Stephen G. Kahler, Mignon McCulloch, Elizabeth Wraige, Lourdes Loidi, Wolfgang Höhne, Ludovic Martin, Smaïl Hadj-Rabia, Robert Terkeltaub, Frank Rutsch  The American Journal of Human Genetics  Volume 90, Issue 1, Pages (January 2012) DOI: /j.ajhg Copyright © 2012 The American Society of Human Genetics Terms and Conditions

2 Figure 1 Manifestation of GACI and PXE Associated with ENPP1 Mutations
Patient 1, who suffered from generalized arterial calcification in infancy. X-ray showing extensive peri-articular calcification of the right shoulder (A) and abdominal CT scan showing a ring-like calcification of the abdominal aorta (B, arrow) in the neonatal period. Yellowish papules, located on the frontal part of the neck when the patient was 9 years old, were suggestive of PXE (C), which was histologically proven by the presence of dermal calcium deposits associated with elastic fibers (D) (Von Kossa staining, ×10). The American Journal of Human Genetics  , 25-39DOI: ( /j.ajhg ) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

3 Figure 2 Schematic Representation of Human NPP1 Shows Mutations Identified in GACI Patients with PXE Features in the Current Study Amino acid positions in functional domains according to spP22413 (SwissProt) = Q5T9R6 (UniProtKB/TREMBL) for human NPP1. The American Journal of Human Genetics  , 25-39DOI: ( /j.ajhg ) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

4 Figure 3 Manifestation of GACI Associated with ABCC6 Mutations
Patient 8, who presented with cyanosis, respiratory distress, and truncal edema on the first day of life. (A) X-ray showing stippled periarticular calcifications of the right shoulder (arrow) and (B) the pelvic cartilage (left arrow) and the left hip joint (right arrow). (C) Abdominal ultrasound showing increased echogenicity of the aortic wall (arrows). (D) A cross-section of a coronary artery from patient 4, who died of myocardial infarction at the age of 6 weeks, shows disruption of the calcified internal elastic lamina (arrows) and massive intima proliferation (HE staining, ×2.5). An asterisk indicates the intraarterial vascular catheter. The American Journal of Human Genetics  , 25-39DOI: ( /j.ajhg ) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

5 Figure 4 Schematic Representation of Human ABCC6 Shows Mutations Identified in GACI Patients in the Current Study A darkened line indicates an ATP binding motif, a circled P indicates a putative phosphoserine, filled-in circles indicate sites of mutations for patients described in this paper, and a dashed line indicates a multi-exon deletion. Abbreviations are as follows: fs, frameshift; ∗, chain termination; del, deletion. Transmembrane helix positions are according to sequence accession number O95255 for human ABCC6. The American Journal of Human Genetics  , 25-39DOI: ( /j.ajhg ) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

6 Figure 5 Multiple Alignment around the Mutation Sites of ABCC6 Sequences from Different Organisms Human, Homo sapiens (O95255); mouse, Mus musculus (Q9R1S7); bovine, Bos taurus (Q8HXQ5); chick, Gallus gallus (Q5F364); frog, Western claw frog, Xenopus tropicalis (A9JRK6); fish, Zebrafish, Danio rerio (Q6PH26); roundworm, Caenorhabditis elegans (Q9N2N3); mosquito, Culex quinquefasciatus (B0W537); fungus, Aspergillus fumigatus (Q4WUC5); and slime mold, Dictyostelium discoideum (Q8T6H3). +, mutant position; fs, frameshift mutation; SM, splice mutation; E, exon; ∗, chain termination; del, deleted residue(s); underlined, ATP-binding motif. The American Journal of Human Genetics  , 25-39DOI: ( /j.ajhg ) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

7 Figure 6 Spectrum of Clinical Manifestations and Affected Tissues Associated with Mutations in ABCC6, ENPP1, and GGCX Mutations of either ABCC6 or ENPP1 can cause the severe phenotype of generalized arterial calcification of infancy, which frequently leads to death within the first year of life. Although mutations in ENPP1 can also cause PXE-like skin lesions and angioid streaks of the retina in children who have GACI and survive the critical period of infancy, mutations in ABCC6 can also manifest later in life with the “classic PXE“ phenotype. Mutations in GGCX are associated with a PXE-like phenotype associated with mild retinopathy, skin calcifications, severe cutis laxa, and deficiency of vitamin-K-dependent clotting factors. Hypophosphatemic rickets has been observed frequently in patients with ENPP1 mutations but here was observed only in one proband carrying a mutation in ABCC6 on one allele. The American Journal of Human Genetics  , 25-39DOI: ( /j.ajhg ) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

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