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

Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6
Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6
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. 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.
0002-9297
25-39
Nitschke, Yvonne
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Baujat, Geneviève
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Botschen, Ulrike
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Wittkampf, Tanja
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Du moulin, Marcel
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Stella, Jacqueline
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Le merrer, Martine
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Guest, Geneviève
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Lambot, Karen
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Tazarourte-pinturier, Marie-frederique
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Chassaing, Nicolas
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Roche, Olivier
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Feenstra, Ilse
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Loechner, Karen
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Deshpande, Charu
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Garber, Samuel j.
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Chikarmane, Rashmi
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Steinmann, Beat
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Shahinyan, Tatevik
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Martorell, Loreto
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Davies, Justin
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Smith, Wendy e.
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Kahler, Stephen g.
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Mcculloch, Mignon
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Wraige, Elizabeth
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Loidi, Lourdes
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Höhne, Wolfgang
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Martin, Ludovic
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Hadj-rabia, Smaïl
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Terkeltaub, Robert
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Rutsch, Frank
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Nitschke, Yvonne
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Baujat, Geneviève
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Botschen, Ulrike
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Wittkampf, Tanja
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Du moulin, Marcel
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Stella, Jacqueline
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Le merrer, Martine
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Guest, Geneviève
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Lambot, Karen
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Tazarourte-pinturier, Marie-frederique
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Chassaing, Nicolas
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Roche, Olivier
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Feenstra, Ilse
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Loechner, Karen
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Deshpande, Charu
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Garber, Samuel j.
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Chikarmane, Rashmi
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Steinmann, Beat
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Shahinyan, Tatevik
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Martorell, Loreto
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Davies, Justin
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Smith, Wendy e.
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Kahler, Stephen g.
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Mcculloch, Mignon
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Wraige, Elizabeth
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Loidi, Lourdes
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Höhne, Wolfgang
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Martin, Ludovic
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Hadj-rabia, Smaïl
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Terkeltaub, Robert
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Rutsch, Frank
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Nitschke, Yvonne, Baujat, Geneviève, Botschen, Ulrike, Wittkampf, Tanja, Du moulin, Marcel, Stella, Jacqueline, Le merrer, Martine, Guest, Geneviève, Lambot, Karen, Tazarourte-pinturier, Marie-frederique, Chassaing, Nicolas, Roche, Olivier, Feenstra, Ilse, Loechner, Karen, Deshpande, Charu, Garber, Samuel j., Chikarmane, Rashmi, Steinmann, Beat, Shahinyan, Tatevik, Martorell, Loreto, Davies, Justin, Smith, Wendy e., Kahler, Stephen g., Mcculloch, Mignon, Wraige, Elizabeth, Loidi, Lourdes, Höhne, Wolfgang, Martin, Ludovic, Hadj-rabia, Smaïl, Terkeltaub, Robert and Rutsch, Frank (2012) Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. The American Journal of Human Genetics, 90 (1), 25-39. (doi:10.1016/j.ajhg.2011.11.020).

Record type: Article

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. 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.

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Published date: 1 January 2012

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Local EPrints ID: 423485
URI: http://eprints.soton.ac.uk/id/eprint/423485
ISSN: 0002-9297
PURE UUID: 2c86073e-e9c7-40b6-b541-7a97fce5831c

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Date deposited: 24 Sep 2018 16:30
Last modified: 15 Mar 2024 21:29

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Contributors

Author: Yvonne Nitschke
Author: Geneviève Baujat
Author: Ulrike Botschen
Author: Tanja Wittkampf
Author: Marcel Du moulin
Author: Jacqueline Stella
Author: Martine Le merrer
Author: Geneviève Guest
Author: Karen Lambot
Author: Marie-frederique Tazarourte-pinturier
Author: Nicolas Chassaing
Author: Olivier Roche
Author: Ilse Feenstra
Author: Karen Loechner
Author: Charu Deshpande
Author: Samuel j. Garber
Author: Rashmi Chikarmane
Author: Beat Steinmann
Author: Tatevik Shahinyan
Author: Loreto Martorell
Author: Justin Davies
Author: Wendy e. Smith
Author: Stephen g. Kahler
Author: Mignon Mcculloch
Author: Elizabeth Wraige
Author: Lourdes Loidi
Author: Wolfgang Höhne
Author: Ludovic Martin
Author: Smaïl Hadj-rabia
Author: Robert Terkeltaub
Author: Frank Rutsch

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