ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification.
ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification.
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DOI：
10.1371/journal.pgen.1010192
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发表时间：
2022-04
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
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弹性假黄瘤（PXE）和婴儿泛发性动脉钙化（GACI）是临床上不同的异位钙化的遗传实体，与无机焦磷酸盐（PPi），一种有效的内源性钙化抑制剂的循环水平差异降低相关。ENPP 1基因的变异体，GACI中的突变基因，与经典的PXE无关。在这里，我们报告的临床，实验室和分子评价10 GACI和PXE患者从5个和两个无关的家庭登记在GACI全球和PXE国际数据库，分别。发现所有患者均携带ENPP 1的双等位基因变体。在10个ENPP 1变异体中，一个纯合变异体表现出单亲二体性遗传。五个以前未报道的ENPP 1变异体的功能评估表明致病性。这两名PXE患者，目前年龄分别为57岁和27岁，具有PXE的诊断特征，但未表现出GACI表型。在我们的研究中，PXE和GACI患者中PPi血浆浓度的类似降低与其疾病严重程度的相关性很差。这项研究表明，除了GACI，ENPP 1变异体可以导致经典的PXE，扩大了遗传性异位钙化疾病的临床和遗传异质性。此外，这些结果挑战了目前流行的概念，即血浆PPi是控制异位钙化严重程度的唯一因素。ENPP 1基因的双等位基因失活突变导致婴儿全身性动脉钙化（GACI），这是一种经常致命的疾病，其特征是婴儿期广泛动脉钙化和/或大中型血管狭窄，通常导致受影响个体的早期死亡。有效的内源性钙化抑制剂无机焦磷酸盐（PPi）的血浆水平显著降低，几乎为零，被认为是GACI血管钙化的根本原因。ENPP 1的突变尚未在弹性假黄瘤（PXE）患者中发现，这是另一种由ABCC 6基因突变引起的遗传性多系统异位钙化疾病。这项研究报告说，ENPP 1突变也可以导致PXE更有利的临床结果。此外，以前认为血浆PPi水平与血管钙化严重程度相关。然而，我们在这里表明，血管钙化的严重程度与血浆PPi水平无关。结果表明，除了PPi，长期认为异位钙化的决定因素，其他机制可能在调节异位钙化。
Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are clinically distinct genetic entities of ectopic calcification associated with differentially reduced circulating levels of inorganic pyrophosphate (PPi), a potent endogenous inhibitor of calcification. Variants in ENPP1, the gene mutated in GACI, have not been associated with classic PXE. Here we report the clinical, laboratory, and molecular evaluations of ten GACI and two PXE patients from five and two unrelated families registered in GACI Global and PXE International databases, respectively. All patients were found to carry biallelic variants in ENPP1. Among ten ENPP1 variants, one homozygous variant demonstrated uniparental disomy inheritance. Functional assessment of five previously unreported ENPP1 variants suggested pathogenicity. The two PXE patients, currently 57 and 27 years of age, had diagnostic features of PXE and had not manifested the GACI phenotype. The similarly reduced PPi plasma concentrations in the PXE and GACI patients in our study correlate poorly with their disease severity. This study demonstrates that in addition to GACI, ENPP1 variants can cause classic PXE, expanding the clinical and genetic heterogeneity of heritable ectopic calcification disorders. Furthermore, the results challenge the current prevailing concept that plasma PPi is the only factor governing the severity of ectopic calcification. Biallelic inactivating mutations in the ENPP1 gene cause generalized arterial calcification of infancy (GACI), a frequently fatal disease characterized by infantile onset of widespread arterial calcification and/or narrowing of large and medium-sized vessels often resulting in the early demise of affected individuals. Significantly reduced, almost zero plasma levels of a potent and endogenous calcification inhibitor, inorganic pyrophosphate (PPi), is thought to be the underlying cause of vascular calcification in GACI. Mutations in ENPP1 have not been found in patients with pseudoxanthoma elasticum (PXE), another genetic multisystem ectopic calcification disorder caused by mutations in the ABCC6 gene. This study reports that ENPP1 mutations can also cause PXE with more favorable clinical outcomes. In addition, it was previously thought that plasma PPi levels correlate with vascular calcification severity. However, we here show that vascular calcification severity does not correlate with plasma PPi levels. The results suggest that in addition to PPi, the long-believed determinant of ectopic calcification, additional mechanisms may be at play in regulating ectopic calcification.
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DOI：
10.1073/pnas.1319582110
发表时间：
2013-12-10
影响因子：
11.1
作者：
Jansen, Robert S.;Kucukosmanoglu, Asli;van de Wetering, Koen
通讯作者：
van de Wetering, Koen
影响因子：
6.5
作者：
Pomozi, Viola;Brampton, Christopher;Fueloep, Krisztina;Chen, Li-Hsieh;Apana, Ailea;Li, Qiaoli;Uitto, Jouni;Le Saux, Olivier;Varadi, Andras
通讯作者：
Varadi, Andras
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
3.6
作者：
Ciana, G;Trappan, A;Rutsch, F
通讯作者：
Rutsch, F
DOI：
10.1111/j.1365-2133.2012.10811.x
发表时间：
2012-05
期刊：
The British journal of dermatology
影响因子：
--
作者：
Li Q;Schumacher W;Jablonski D;Siegel D;Uitto J
通讯作者：
Uitto J