Kozák Eszter, Bartstra Jonas W, de Jong Pim A, Mali Willem P T M, Fülöp Krisztina, Tőkési Natália, Pomozi Viola, Risseeuw Sara, Norel Jeannette Ossewaarde-van, van Leeuwen Redmer, Váradi András, Spiering Wilko
Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Sciences Center of Excellence, 1117 Budapest, Hungary.
Department of Radiology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands.
J Clin Med. 2023 Jan 29;12(3):1047. doi: 10.3390/jcm12031047.
Pseudoxanthoma elasticum (PXE), a monogenic disorder resulting in calcification affecting the skin, eyes and peripheral arteries, is caused by mutations in the ABCC6 gene, and is associated with low plasma inorganic pyrophosphate (PP). It is unknown how ABCC6 genotype affects plasma PP.
We studied the association of ABCC6 genotype (192 patients with biallelic pathogenic ABCC6 mutations) and PP levels, and its association with the severity of arterial and ophthalmological phenotypes. ABCC6 variants were classified as truncating or non-truncating, and three groups of the 192 patients were formed: those with truncating mutations on both chromosomes ( = 121), those with two non-truncating mutations ( = 10), and a group who had one truncating and one non-truncating ABCC6 mutation ( = 61). The hypothesis formulated before this study was that there was a negative association between PP level and disease severity.
Our findings confirm low PP in PXE compared with healthy controls (0.53 ± 0.15 vs. 1.13 ± 0.29 µM, < 0.01). The PP of patients correlated with increasing age (β: 0.05 µM, 95% CI: 0.03-0.06 per 10 years) and was higher in females (0.55 ± 0.17 vs. 0.51 ± 0.13 µM in males, = 0.03). However, no association between PP and PXE phenotypes was found. When adjusted for age and sex, no association between PP and ABCC6 genotype was found.
Our data suggest that the relationship between ABCC6 mutations and reduced plasma PP may not be as direct as previously thought. PP levels varied widely, even in patients with the same ABCC6 mutations, further suggesting a lack of direct correlation between them, even though the ABCC6 protein-mediated pathway is responsible for ~60% of this metabolite in the circulation. We discuss potential factors that may perturb the expected associations between ABCC6 genotype and PP and between PP and disease severity. Our findings support the argument that predictions of pathogenicity made on the basis of mutations (or on the structure of the mutated protein) could be misleading.
弹性假黄瘤（PXE）是一种单基因疾病，会导致皮肤、眼睛和外周动脉钙化，由ABCC6基因突变引起，与血浆无机焦磷酸（PP）水平降低有关。目前尚不清楚ABCC6基因型如何影响血浆PP水平。
我们研究了ABCC6基因型（192例携带双等位基因致病性ABCC6突变的患者）与PP水平的关联，以及其与动脉和眼科表型严重程度的关联。ABCC6变异被分类为截短型或非截短型，192例患者被分为三组：两条染色体均有截短突变的患者（n = 121）、有两个非截短突变的患者（n = 10）以及有一个截短型和一个非截短型ABCC6突变的患者（n = 61）。本研究之前提出的假设是PP水平与疾病严重程度呈负相关。
我们的研究结果证实，与健康对照相比，PXE患者的PP水平较低（0.53±0.15 vs. 1.13±0.29 μM，P < 0.01）。患者的PP水平与年龄增长相关（β：0.05 μM，95%置信区间：每10年0.03 - 0.06），女性的PP水平更高（0.55±0.17 vs.男性的0.51±0.13 μM，P = 0.03）。然而，未发现PP与PXE表型之间存在关联。在对年龄和性别进行校正后，未发现PP与ABCC6基因型之间存在关联。
我们的数据表明，ABCC6突变与血浆PP降低之间的关系可能不像之前认为的那样直接。即使是具有相同ABCC6突变的患者，PP水平也存在很大差异，这进一步表明它们之间缺乏直接相关性，尽管ABCC6蛋白介导的途径负责循环中约60%的这种代谢物。我们讨论了可能扰乱ABCC6基因型与PP之间以及PP与疾病严重程度之间预期关联的潜在因素。我们的研究结果支持了基于突变（或突变蛋白结构）进行致病性预测可能会产生误导这一观点。
