Dataset Information

Cutaneous features of pseudoxanthoma elasticum in a patient with generalized arterial calcification of infancy due to a homozygous missense mutation in the ENPP1 gene.

ABSTRACT: Pseudoxanthoma elasticum (PXE) manifests with cutaneous lesions consisting of yellowish papules coalescing into plaques of inelastic skin. Histopathology demonstrates accumulation of pleiomorphic elastic structures with progressive mineralization. The classic form of PXE is caused by mutations in the ABCC6 gene.A 2-year-old patient with PXE of the neck, inguinal folds and lower abdomen, and with extensive tissue mineralization, was evaluated for the underlying mutations in candidate genes known to be involved in ectopic mineralization disorders.The patient's genotype was studied by sequencing ABCC6, MGP and ENPP1 genes, encoding proteins which harbour mutations in ectopic mineralization disorders.No pathogenetic mutations were found in the ABCC6 or MGP genes. Sequencing of ENPP1 disclosed a homozygous missense mutation, p.Y513C, associated with generalized arterial calcification of infancy.This study demonstrates the presence of the cutaneous features of PXE in a genetically distinct disease, generalized arterial calcification of infancy, and thus expands the spectrum of PXE-related disorders.

SUBMITTER: Li Q

PROVIDER: S-EPMC3336007 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Cutaneous features of pseudoxanthoma elasticum in a patient with generalized arterial calcification of infancy due to a homozygous missense mutation in the ENPP1 gene.

Li Q Q Schumacher W W Jablonski D D Siegel D D Uitto J J

The British journal of dermatology 20120404 5

<h4>Background</h4>Pseudoxanthoma elasticum (PXE) manifests with cutaneous lesions consisting of yellowish papules coalescing into plaques of inelastic skin. Histopathology demonstrates accumulation of pleiomorphic elastic structures with progressive mineralization. The classic form of PXE is caused by mutations in the ABCC6 gene.<h4>Objectives</h4>A 2-year-old patient with PXE of the neck, inguinal folds and lower abdomen, and with extensive tissue mineralization, was evaluated for the underlyi ...[more]

PMID: 22229486

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Project description:In recent years it has become clear that, mechanistically, biomineralization is a process that has to be actively inhibited as a default state. This inhibition must be released in a rigidly controlled manner in order for mineralization to occur in skeletal elements and teeth. A central aspect of this concept is the tightly controlled balance between phosphate, a constituent of the biomineral hydroxyapatite, and pyrophosphate, a physiochemical inhibitor of mineralization. Here, we provide a detailed analysis of a zebrafish mutant, dragonfish (dgf), which is mutant for ectonucleoside pyrophosphatase/phosphodiesterase 1 (Enpp1), a protein that is crucial for supplying extracellular pyrophosphate. Generalized arterial calcification of infancy (GACI) is a fatal human disease, and the majority of cases are thought to be caused by mutations in ENPP1. Furthermore, some cases of pseudoxanthoma elasticum (PXE) have recently been linked to ENPP1. Similar to humans, we show here that zebrafish enpp1 mutants can develop ectopic calcifications in a variety of soft tissues - most notably in the skin, cartilage elements, the heart, intracranial space and the notochord sheet. Using transgenic reporter lines, we demonstrate that ectopic mineralizations in these tissues occur independently of the expression of typical osteoblast or cartilage markers. Intriguingly, we detect cells expressing the osteoclast markers Trap and CathepsinK at sites of ectopic calcification at time points when osteoclasts are not yet present in wild-type siblings. Treatment with the bisphosphonate etidronate rescues aspects of the dgf phenotype, and we detected deregulated expression of genes that are involved in phosphate homeostasis and mineralization, such as fgf23, npt2a, entpd5 and spp1 (also known as osteopontin). Employing a UAS-GalFF approach, we show that forced expression of enpp1 in blood vessels or the floorplate of mutant embryos is sufficient to rescue the notochord mineralization phenotype. This indicates that enpp1 can exert its function in tissues that are remote from its site of expression.

Dataset Information

Cutaneous features of pseudoxanthoma elasticum in a patient with generalized arterial calcification of infancy due to a homozygous missense mutation in the ENPP1 gene.

Publications

Cutaneous features of pseudoxanthoma elasticum in a patient with generalized arterial calcification of infancy due to a homozygous missense mutation in the ENPP1 gene.

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