Mutations in the ABCC6 Gene as a Cause of Generalized Arterial Calcification of Infancy: Genotypic Overlap with Pseudoxanthoma Elasticum Qiaoli Li, Jill.

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Mutations in the ABCC6 Gene as a Cause of Generalized Arterial Calcification of Infancy: Genotypic Overlap with Pseudoxanthoma Elasticum Qiaoli Li, Jill L. Brodsky, Laura K. Conlin, Bruce Pawel, Andrew C. Glatz, Rachel I. Gafni, Leon Schurgers, Jouni Uitto, Hakon Hakonarson, Matthew A. Deardorff, Michael A. Levine Journal of Investigative Dermatology Volume 134, Issue 3, Pages 658-665 (March 2014) DOI: 10.1038/jid.2013.370 Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Nuclear pedigrees of Families A–F with generalized arterial calcification of infancy. The mutations discovered in the ABCC6 gene in the individual family members are indicated below each individual: +/+, homozygous for the wild-type allele; +/-, heterozygous carrier; −/−, mutations in both alleles. Journal of Investigative Dermatology 2014 134, 658-665DOI: (10.1038/jid.2013.370) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Ultrasound and histopathologic features in individuals with generalized arterial calcification of infancy (GACI). (a) Ultrasound of patient 1 in Family A (II-3) reveals, in lateral sagittal view of head, calcifications along the cores of lenticulostriate vessels (arrow). (b–d) Histopathology of patient 3 in Family B (II-1) shows calcification of mesenteric artery (b), abdominal artery (c), and left renal artery (d); hematoxylin-eosin stain, original magnifications × 150. (e) Patient 6 in Family E (II-1) demonstrated by ultrasound imaging portions of the proximal external carotid artery with thickened walls and irregular, speckled calcification (arrows). (f) Patient 7 in Family F (II-3), prenatal ultrasound of aortic bifurcation demonstrates extensive calcification (arrows). Journal of Investigative Dermatology 2014 134, 658-665DOI: (10.1038/jid.2013.370) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Mutation analysis of the ABCC6 gene in Family A with generalized arterial calcification of infancy (GACI). Sequencing of the ABCC6 gene in patients 1 and 2 (II-3 and II-4 in Figure 1) revealed a homozygous nucleotide T substitution (b) replacing nucleotide C in the control DNA (a). This mutation results in substitution of arginine (R) by tryptophan (W) at amino-acid position 1314. The arginine residue is well conserved through evolution (c). Journal of Investigative Dermatology 2014 134, 658-665DOI: (10.1038/jid.2013.370) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Immunofluorescence of the presence of carboxylated (active, cMGP) and uncarboxylated (inactive, ucMGP) forms of matrix gla protein (MGP) and fetuin-A in patient 3 in Family B (II-1). Immunofluorescence with antibodies recognizing carboxylated (a) and uncarboxylated (b) forms of MGP and fetuin-A (c). Frames (d–f) represent the corresponding negative controls in which the primary antibodies were omitted. Journal of Investigative Dermatology 2014 134, 658-665DOI: (10.1038/jid.2013.370) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions