Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The VSports app下载. gov means it’s official. Federal government websites often end in . gov or . mil. Before sharing sensitive information, make sure you’re on a federal government site. .

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely V体育官网. .

. 2012 Jan 13;90(1):25-39.
doi: 10.1016/j.ajhg.2011.11.020. Epub 2011 Dec 29.

Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6

Yvonne Nitschke  1 , 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
Affiliations

Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6

Yvonne Nitschke et al. Am J Hum Genet. .

Abstract

Spontaneous pathologic arterial calcifications in childhood can occur in generalized arterial calcification of infancy (GACI) or in pseudoxanthoma elasticum (PXE). GACI is associated with biallelic mutations in ENPP1 in the majority of cases, whereas mutations in ABCC6 are known to cause PXE VSports手机版. However, the genetic basis in subsets of both disease phenotypes remains elusive. We hypothesized that GACI and PXE are in a closely related spectrum of disease. We used a standardized questionnaire to retrospectively evaluate the phenotype of 92 probands with a clinical history of GACI. We obtained the ENPP1 genotype by conventional sequencing. In those patients with less than two disease-causing ENPP1 mutations, we sequenced ABCC6. We observed that three GACI patients who carried biallelic ENPP1 mutations developed typical signs of PXE between 5 and 8 years of age; these signs included angioid streaks and pseudoxanthomatous skin lesions. In 28 patients, no disease-causing ENPP1 mutation was found. In 14 of these patients, we detected pathogenic ABCC6 mutations (biallelic mutations in eight patients, monoallelic mutations in six patients). Thus, ABCC6 mutations account for a significant subset of GACI patients, and ENPP1 mutations can also be associated with PXE lesions in school-aged children. Based on the considerable overlap of genotype and phenotype of GACI and PXE, both entities appear to reflect two ends of a clinical spectrum of ectopic calcification and other organ pathologies, rather than two distinct disorders. ABCC6 and ENPP1 mutations might lead to alterations of the same physiological pathways in tissues beyond the artery. .

PubMed Disclaimer

VSports - Figures

Figure 1
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).
Figure 2
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.
Figure 3
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.
Figure 4
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.
Figure 5
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.
Figure 6
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.
See this image and copyright information in PMC

References

    1. Rutsch F., Vaingankar S., Johnson K., Goldfine I., Maddux B., Schauerte P., Kalhoff H., Sano K., Boisvert W.A., Superti-Furga A., Terkeltaub R. PC-1 nucleoside triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification. Am. J. Pathol. 2001;158:543–554. - PMC - PubMed
    1. Moran J.J. Idiopathic arterial calcification of infancy: A clinicopathologic study. Pathol. Annu. 1975;10:393–417. - PubMed
    1. Morton R. Idiopathic arterial calcification in infancy. Histopathology. 1978;2:423–432. - PubMed
    1. Stuart G., Wren C., Bain H. Idiopathic infantile arterial calcification in two siblings: Failure of treatment with diphosphonate. Br. Heart J. 1990;64:156–159. - PMC - PubMed
    1. Ramjan K.A., Roscioli T., Rutsch F., Sillence D., Munns C.F. Generalized arterial calcification of infancy: Treatment with bisphosphonates. Nat. Clin. Pract. Endocrinol. Metab. 2009;5:167–172. - PubMed

Publication types

MeSH terms

Substances

Supplementary concepts