Retinitis Pigmentosa, Cutis Laxa, and Pseudoxanthoma Elasticum–Like Skin Manifestations Associated with GGCX Mutations Ariana Kariminejad, Bita Bozorgmehr,

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Retinitis Pigmentosa, Cutis Laxa, and Pseudoxanthoma Elasticum–Like Skin Manifestations Associated with GGCX Mutations Ariana Kariminejad, Bita Bozorgmehr, Abdolhamid Najafi, Atefeh Khoshaeen, Maryam Ghalandari, Hossein Najmabadi, Mohamad H. Kariminejad, Olivier M. Vanakker, Mohammad J. Hosen, Fransiska Malfait, Daniela Quaglino, Ralph J. Florijn, Arthur A.B. Bergen, Raoul C. Hennekam Journal of Investigative Dermatology Volume 134, Issue 9, Pages 2331-2338 (September 2014) DOI: 10.1038/jid.2014.191 Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Pedigrees and clinical characteristics of the two families. (a, b) Affected individuals are indicated with black symbols. Journal of Investigative Dermatology 2014 134, 2331-2338DOI: (10.1038/jid.2014.191) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Clinical findings and fundus image of proband. (a, b) Excessive skin folds and leathery texture mostly prominent in the trunk. (c, d) Note yellowish papules and depressed dots in the neck. (e) Fundus of affected individual V12 of family 1 (Figure 1) showing characteristics of retinitis pigmentosa (RP). Journal of Investigative Dermatology 2014 134, 2331-2338DOI: (10.1038/jid.2014.191) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Histology of skin lesions using light and electron microscopy. (a) Full-thickness overview of the affected skin shows thin and fragmented elastic fibers in areas 1 through 4. Only in area 5 can mineralization of the fragmented elastic fibers be assumed. This is further documented using Alizarin red staining (b; original magnification × 20), showing extensive labeling in the deeper dermis, whereas only limited mineralization is observed in the reticular and mid-dermis. High-resolution electron microscopy of the deeper dermis shows mineralization in the core and periphery of the affected elastic fibers (c–e; asterisks). Collagen fibers show some variation, some being small, but no other abnormalities. Scale bar=1μm. Journal of Investigative Dermatology 2014 134, 2331-2338DOI: (10.1038/jid.2014.191) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Immunohistochemistry for uncarboxylated (uc) matrix gla protein (MGP). (a) Alizarin red staining of the examined skin fragments. All tissues were fragile and heavily fragmented, probably because of the disease itself. (b) Staining for ucMGP shows positive labeling compared with a negative control (c). The staining, which is clumped (d), resembles staining of ucMGP in the pseudoxanthoma elasticum (PXE)-like syndrome with coagulation factor deficiency (e), although in the latter ucMGP is more abundant. Scale bar=200μm. Journal of Investigative Dermatology 2014 134, 2331-2338DOI: (10.1038/jid.2014.191) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Gamma-glutamyl carboxylase (GGCX) (accession number NM_000821.4) exons were sequenced in DNA samples of this family. (a) Chromatograms of the identified sequence change c.373+3 G>T are shown for a homozygous, heterozygous, and consensus sequence. The lower bar schematically shows the exon/intron structure of GGCX exon 3. (b) The c.373+3G>T sequence change causing a skip of exon 3 in the GGCX mRNA. (b) Wild-type cDNA sequence; (c) patient cDNA sequence. Journal of Investigative Dermatology 2014 134, 2331-2338DOI: (10.1038/jid.2014.191) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions