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Genetic heterogeneity of heritable ectopic mineralization disorders in a large international cohort.Genetics in Medicine : Official Journal... Jan 2022Heritable ectopic mineralization disorders comprise a group of conditions with a broad range of clinical manifestations in nonskeletal connective tissues. We report the...
PURPOSE
Heritable ectopic mineralization disorders comprise a group of conditions with a broad range of clinical manifestations in nonskeletal connective tissues. We report the genetic findings from a large international cohort of 478 patients afflicted with ectopic mineralization.
METHODS
Sequence variations were identified using a next-generation sequencing panel consisting of 29 genes reported in association with ectopic mineralization. The pathogenicity of select splicing and missense variants was analyzed in experimental systems in vitro and in vivo.
RESULTS
A total of 872 variants of unknown significance as well as likely pathogenic and pathogenic variants were disclosed in 25 genes. A total of 159 distinct variants were identified in 425 patients in ABCC6, the gene responsible for pseudoxanthoma elasticum, a heritable multisystem ectopic mineralization disorder. The interpretation of variant pathogenicity relying on bioinformatic predictions did not provide a consensus. Our in vitro and in vivo functional assessment of 14 ABCC6 variants highlighted this dilemma and provided unambiguous interpretations to their pathogenicity.
CONCLUSION
The results expand the ABCC6 variant repertoire, shed new light on the genetic heterogeneity of heritable ectopic mineralization disorders, and provide evidence that functional characterization in appropriate experimental systems is necessary to determine the pathogenicity of genetic variants.
Topics: Cohort Studies; Connective Tissue; Genetic Heterogeneity; Humans; Mutation, Missense; Pseudoxanthoma Elasticum
PubMed: 34906475
DOI: 10.1016/j.gim.2021.08.011 -
Eye (London, England) Mar 2022
Topics: Angioid Streaks; Humans; Pseudoxanthoma Elasticum; Vision Disorders
PubMed: 34862446
DOI: 10.1038/s41433-021-01858-7 -
Experimental Dermatology Apr 2022Pseudoxanthoma elasticum (PXE; OMIM 264800) is a rare heritable multisystem disorder, characterized by ectopic mineralization affecting elastic fibres in the skin, eyes...
Pseudoxanthoma elasticum (PXE; OMIM 264800) is a rare heritable multisystem disorder, characterized by ectopic mineralization affecting elastic fibres in the skin, eyes and the cardiovascular system. Skin findings often lead to early diagnosis of PXE, but currently, no specific treatment exists to counteract the progression of symptoms. PXE belongs to a group of Mendelian calcification disorders linked to pyrophosphate metabolism, which also includes generalized arterial calcification of infancy (GACI) and arterial calcification due to CD73 deficiency (ACDC). Inactivating mutations in ABCC6, ENPP1 and NT5E are the genetic cause of these diseases, respectively, and all of them result in reduced inorganic pyrophosphate (PP ) concentration in the circulation. Although PP is a strong inhibitor of ectopic calcification, oral supplementation therapy was initially not considered because of its low bioavailability. Our earlier work however demonstrated that orally administered pyrophosphate inhibits ectopic calcification in the animal models of PXE and GACI, and that orally given Na P O is absorbed in humans. Here, we report that gelatin-encapsulated Na H P O has similar absorption properties in healthy volunteers and people affected by PXE. The sodium-free K H P O form resulted in similar uptake in healthy volunteers and inhibited calcification in Abcc6 mice as effectively as its sodium counterpart. Novel pyrophosphate compounds showing higher bioavailability in mice were also identified. Our results provide an important step towards testing oral PP in clinical trials in PXE, or potentially any condition accompanied by ectopic calcification including diabetes, chronic kidney disease or ageing.
Topics: Animals; Dietary Supplements; Diphosphates; Humans; Mice; Mutation; Phosphoric Diester Hydrolases; Pseudoxanthoma Elasticum; Pyrophosphatases; Vascular Calcification
PubMed: 34758173
DOI: 10.1111/exd.14498 -
Cureus Oct 2021Pseudoxanthoma elasticum (PXE) is a rare, autosomal recessive connective tissue disease that manifests primarily in the skin, eyes, vasculature, and gastrointestinal...
Pseudoxanthoma elasticum (PXE) is a rare, autosomal recessive connective tissue disease that manifests primarily in the skin, eyes, vasculature, and gastrointestinal tract. Most cases occur in women and are present in the third decade of life. Diagnosis is confirmed via skin biopsy or by genetic testing that reveals a variant gene. We present the case of a 68-year-old woman who came to the clinic to discuss her daughter's diagnosis of PXE, specifically, what testing she and her family should pursue. A family pedigree revealed a strong family history of abdominal aortic aneurysm (AAA). Although PXE has not been directly related to AAA, this raised concern for familial connective tissue disease. It was recommended that all family members undergo AAA screening with ultrasound, but that not all family members warranted genetic testing. Patients diagnosed with PXE should establish care with specialists to monitor for adverse outcomes.
PubMed: 34754643
DOI: 10.7759/cureus.18481 -
The Journal of Investigative Dermatology Jun 2022Pseudoxanthoma elasticum (PXE) is a hereditary ectopic calcification disorder affecting the skin, eyes, and blood vessels. Recently, the DNA damage response (DDR), in...
Pseudoxanthoma elasticum (PXE) is a hereditary ectopic calcification disorder affecting the skin, eyes, and blood vessels. Recently, the DNA damage response (DDR), in particular PARP1, was shown to be involved in aberrant mineralization, raising the hypothesis that excessive DDR/PARP1 signaling also contributes to PXE pathogenesis. Using dermal fibroblasts of patients with PXE and healthy controls, (lesional) skin tissue, and abcc6a zebrafish, we performed expression analysis of DDR/PARP1 targets with QRT-PCR, western blot, immunohistochemistry, and enzyme activity assays before and after treatment with the PARP1 inhibitor minocycline. PARP1 and the ATM‒p21‒p53 axis was found to be significantly increased in PXE. In addition, PARP1 downstream targets IL-6, signal transducer and activator of transcription 1/3, TET1, and RUNX2 were upregulated, whereas the RUNX2 antagonist microRNA-204 was decreased. In PXE fibroblasts, DDR/PARP1 signaling increased with advancing ectopic calcification. Minocycline treatment attenuated DDR/PARP1 overexpression and reduced aberrant mineralization in PXE fibroblasts and abcc6a zebrafish. In summary, we showed the involvement of excessive DDR/PARP1 signaling in PXE pathophysiology, identifying a signal transducer and activator of transcription‒driven cascade resulting in increased expression of the epigenetic modifier TET1 and procalcifying transcription factor RUNX2. Minocycline attenuated this deleterious molecular mechanism and reduced ectopic calcification both in vitro and in vivo, fueling the exciting prospect of a therapeutic compound for PXE.
Topics: ATP-Binding Cassette Transporters; Animals; Core Binding Factor Alpha 1 Subunit; DNA Damage; Humans; MicroRNAs; Minocycline; Mixed Function Oxygenases; Multidrug Resistance-Associated Proteins; Proto-Oncogene Proteins; Pseudoxanthoma Elasticum; Zebrafish; Zebrafish Proteins
PubMed: 34742705
DOI: 10.1016/j.jid.2021.10.019 -
Diagnostics (Basel, Switzerland) Sep 2021A 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....
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 , , and 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.
PubMed: 34679498
DOI: 10.3390/diagnostics11101800 -
JTCVS Techniques Oct 2021
PubMed: 34647055
DOI: 10.1016/j.xjtc.2021.07.028 -
JTCVS Techniques Oct 2021
PubMed: 34647054
DOI: 10.1016/j.xjtc.2021.07.022 -
JTCVS Techniques Oct 2021
PubMed: 34647053
DOI: 10.1016/j.xjtc.2021.07.008 -
The Journal of Investigative Dermatology Apr 2022Pseudoxanthoma elasticum, a heritable multisystem ectopic mineralization disorder, is caused by inactivating mutations in the ABCC6 gene. The encoded protein, ABCC6, a...
Pseudoxanthoma elasticum, a heritable multisystem ectopic mineralization disorder, is caused by inactivating mutations in the ABCC6 gene. The encoded protein, ABCC6, a transmembrane transporter, has a specialized efflux function in hepatocytes by contributing to plasma levels of inorganic pyrophosphate, a potent inhibitor of mineralization in soft connective tissues. Reduced plasma inorganic pyrophosphate levels underlie the ectopic mineralization in pseudoxanthoma elasticum. In this study, we characterized the pathogenicity of three human ABCC6 missense variants using an adenovirus-mediated liver-specific ABCC6 transgene expression system in an Abcc6 mouse model of pseudoxanthoma elasticum. Variants p.L420V and p.R1064W were found benign because they had abundance and plasma membrane localization in hepatocytes similar to the wild-type human ABCC6 transgene, normalized plasma inorganic pyrophosphate levels, and prevented mineralization in the dermal sheath of vibrissae in muzzle skin, a phenotypic hallmark in the Abcc6 mice. In contrast, p.S400F was shown to be pathogenic because it failed to normalize plasma inorganic pyrophosphate levels and had no effect on ectopic mineralization despite its normal expression and proper localization in hepatocytes. These results showed that adenovirus-mediated hepatic ABCC6 expression in Abcc6 mice can provide a model system to effectively elucidate the multifaceted functional consequences of human ABCC6 missense variants identified in patients with pseudoxanthoma elasticum.
Topics: Adenoviridae; Animals; Calcinosis; Diphosphates; Disease Models, Animal; Humans; Mice; Multidrug Resistance-Associated Proteins; Mutation, Missense; Pseudoxanthoma Elasticum; Skin
PubMed: 34597610
DOI: 10.1016/j.jid.2021.08.435