Molecular Genetics and Modifier Genes in Pseudoxanthoma Elasticum, a Heritable Multisystem Ectopic Mineralization Disorder

Luo, Huimin; Faghankhani, Masoomeh; Cao, Yi; Uitto, Jouni; Li, Qiaoli

doi:10.1016/j.jid.2020.10.013

Cited by 21 publications

(24 citation statements)

References 120 publications

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“…The identification and contribution of peripheral tissues to calcification regulation remains unresolved. Plasma PPi levels fail to explain the wide range of calcification severity in humans [ 17 ] and mice [ 111 ] ( Cf Figure 1 ) and the clinical relevance of potential modifier genes [ 109 , 110 , 147 , 150 , 154 , 155 , 156 ] is still unknown. Finally, what is (if any) the role of inflammation in the progression of PXE [ 159 ]?…”

Section: Discussionmentioning

confidence: 99%

“…Pancreatic islet hyperplasia was observed as well as fibro-osseous lesions in several bones. More interesting is that these strains of mice carry the exact same Abcc6 gene mutation and have similar plasma PPi levels ( Figure 2 ), which clearly underlie the possible role of other factors such as the environment [ 19 ] and/or modifier genes in the development of ectopic calcification [ 109 , 110 ].…”

Section: Animal Modelsmentioning

confidence: 99%

“…However, a very recent clinical study performed with 289 PXE patients found that mixed genotype led to less severe arterial calcification and ocular manifestations than patients with two truncating ABCC6 variants and suggested that environmental or modifier genes could also contribute to the still unexplained phenotypic variability in PXE [ 153 ]. The presence of modifier genes modulating calcification in PXE has been investigated in human and mice but their predictive values for clinical applications are not clear [ 109 , 110 , 147 , 150 , 154 , 155 , 156 ]. Moreover, PXE is a slow and chronic disease with stepwise progression of the phenotype occurring over a period of time measured in years, if not decades [ 157 ].…”

Section: Rescue and Therapeutic Solutionsmentioning

confidence: 99%

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ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

Shimada

Pomozi

Zoll

et al. 2021

IJMS

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Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the “PXE gene” and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds.

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Section: Discussionmentioning

confidence: 99%

Section: Animal Modelsmentioning

confidence: 99%

Section: Rescue and Therapeutic Solutionsmentioning

confidence: 99%

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ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

Shimada

Pomozi

Zoll

et al. 2021

IJMS

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“…In order to investigate the involvement of other genes, we conducted a whole exome sequencing analysis, performed as already described ( 11 ), focusing on 362 genes of which 41 ( Supplementary Table 1 ) have been associated with calcification-related diseases, according to UniProtKB, or with the mineralization process ( 8 , 9 ), whereas 321 genes (RetNet, https://sph.uth.edu/retnet/ ) were known as causative of inherited retinal diseases (e.g., macular degeneration, Stargardt disease, retinal atrophy). Using a human genomic variant search engine (VarSome; https://varsome.com ) ( 12 ), detected rare sequence variants (RSV) were classified as benign, likely benign, uncertain significance, likely pathogenic and pathogenic, according to the guidelines of American College of Medical Genetics and Genomics and the Association for Molecular Pathology ( 13 ).…”

Section: Case Reportmentioning

confidence: 99%

From Clinical Diagnosis to the Discovery of Multigene Rare Sequence Variants in Pseudoxanthoma elasticum: A Case Report

et al. 2021

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Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disease clinically characterised by early cutaneous alterations, and by late clinically relevant ocular, and cardiovascular manifestations. ABCC6 genetic tests are used to confirm clinical PXE diagnosis, but this strategy may be rather challenging when only one ABCC6 pathogenic variant is found. A next-generation sequencing approach focusing on 362 genes related to the calcification process and/or to inherited retinal diseases was performed on a patient with clinical PXE diagnosis (skin papules and laxity, angioid streaks, and atrophy) who was carrier of only one ABCC6 rare sequence variant. Beside ABCC6, several rare sequence variants were detected which can contribute either to the occurrence of calcification (GGCX and SERPINF1 genes) and/or to ophthalmological manifestations (ABCA4, AGBL5, CLUAP1, and KCNV2 genes). This wide-spectrum analysis approach facilitates the identification of rare variants possibly involved in PXE, thus avoiding invasive skin biopsy as well as expensive and time-consuming diagnostic odyssey and allows to broaden and to deepen the knowledge on this complex rare disease and to improve patients' counselling, also with a future perspective of personalised medicine.

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“…Inheritance of PXE is on an autosomal recessive basis and is mainly due to pathogenic variants in the ABCC6 gene [8], although in the last few years, the presence of pathogenic variants in calcification-related genes (e.g., vitamin K-dependent gamma-carboxylase (GGCX) or ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1)) has also been demonstrated [9][10][11]. Recently, the involvement of modifier genes has also been proposed [12]. For instance, pathogenic variants in ABCA4 and in USH2A genes (i.e., genes responsible for inherited retinal diseases (IRDs)) were described in PXE patients [13,14] and these findings are of particular interest as IRDs are a group of genotypically and phenotypically heterogeneous diseases that are characterized by ocular manifestations similar to those observed in PXE.…”

Section: Introductionmentioning

confidence: 99%

A Case Report of Pseudoxanthoma Elasticum with Rare Sequence Variants in Genes Related to Inherited Retinal Diseases

et al. 2021

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A case of a patient with an early and severe visual impairment is described. Due to the occurrence of skin papules a suspect of pseudoxanthoma elasticum (PXE) was posed. PXE is a rare autosomal recessive disease clinically characterized by skin, cardiovascular and ocular manifestations, these last being those that most severely affect patients’ quality of life. A whole exome sequencing approach focusing on 340 genes related to the calcification process and/or to inherited retinal diseases (IRDs) was performed. Rare monoallelic sequence variants in ABCA4, ABCC6, IMPG1, POC1B and RAX2 were found. The presence of calcified elastic fibers was assessed by ultrastructural analysis on a skin biopsy. Diagnosis of PXE was based on clinical, biomolecular and morphological results, although the additional involvement of several IRD genes is important to explain the unexpectedly severe ophthalmological phenotype of the patient also in prognostic and therapeutic perspectives. Data indicate that genetic screening using a wide-spectrum analysis approach is essential to assist ophthalmologists in improving patient counseling.

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Molecular Genetics and Modifier Genes in Pseudoxanthoma Elasticum, a Heritable Multisystem Ectopic Mineralization Disorder

Cited by 21 publications

References 120 publications

ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

From Clinical Diagnosis to the Discovery of Multigene Rare Sequence Variants in Pseudoxanthoma elasticum: A Case Report

A Case Report of Pseudoxanthoma Elasticum with Rare Sequence Variants in Genes Related to Inherited Retinal Diseases

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