An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature
An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature
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DOI：
10.1210/clinem/dgaa190
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发表时间：
2020-07-01
影响因子：
5.8
通讯作者：
van der Kaay, Danielle C. M.
中科院分区：
文献类型：
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作者：
Lauffer, Peter;Miranda-Laferte, Erick;van der Kaay, Danielle C. M.
背景：C型利钠肽(CNP)与软骨内骨生长密切相关。编码CNP或其形成受体的环鸟苷(CGMP)受体(钠尿肽受体B[NPR-B]，基因NPR2)的基因变异导致单基因生长障碍。在这里，我们描述了一种新的与高个子和大趾趾相关的NPR-B功能获得变异体(骨骺软骨发育不良，Miura类型)。设计：收集了3个家庭成员的历史和临床特征。选择NPR2进行测序。用皮肤成纤维细胞和转染的HEK-293细胞比较突变型和野生型NPR-B的活性。结果：母亲身高标准差得分为+2.77。她的2个女儿的身高在7岁时为+1.96，在4岁时为+1.30。骨骼测量显示大指趾和中近节指骨的假性骨痂。测序发现NPR2基因第8外显子有一个新的杂合突变c.1444_1449delATGCTG，预测导致NPR-B亚膜区2个氨基酸Met482-Leu483的缺失。先证者皮肤成纤维细胞基础cGMP水平和CNP刺激的cGMP产量均显著高于对照组。与HEK-293细胞的检测结果一致显示，突变型NPR-B的基线活性和配体依赖活性显著增强。结论：我们报道了NPR-B胞内亚区的第二个激活变异体，导致身材矮小和大趾畸形。我们的功能和模型研究表明，该结构域在cGMP生产所需的NPR-B的基线构象和配体依赖的结构重排中发挥关键作用。
Context: C-type natriuretic peptide (CNP) is critically involved in endochondral bone growth. Variants in the genes encoding CNP or its cyclic guanosine monophosphate (cGMP)-forming receptor (natriuretic peptide receptor-B [NPR-B], gene NPR2) cause monogenic growth disorders. Here we describe a novel gain-of-function variant of NPR-B associated with tall stature and macrodactyly of the great toes (epiphyseal chondrodysplasia, Miura type).Design: History and clinical characteristics of 3 family members were collected. NPR2 was selected for sequencing. Skin fibroblasts and transfected HEK-293 cells were used to compare mutant versus wild-type NPR-B activities. Homology modeling was applied to understand the molecular consequences of the variant.Results: Mother's height was +2.77 standard deviation scores (SDS). The heights of her 2 daughters were +1.96 SDS at 7 years and +1.30 SDS at 4 years of age. Skeletal surveys showed macrodactyly of the great toes and pseudo-epiphyses of the mid- and proximal phalanges. Sequencing identified a novel heterozygous variant c.1444_1449delATGCTG in exon 8 of NPR2, predicted to result in deletion of 2 amino acids Met482-Leu483 within the submembrane region of NPR-B. In proband's skin fibroblasts, basal cGMP levels and CNP-stimulated cGMP production were markedly increased compared with controls. Consistently, assays with transfected HEK-293 cells showed markedly augmented baseline and ligand-dependent activity of mutant NPR-B.Conclusions: We report the second activating variant within the intracellular submembrane region of NPR-B resulting in tall stature and macrodactyly. Our functional and modeling studies suggest that this domain plays a critical role in the baseline conformation and ligand-dependent structural rearrangement of NPR-B required for cGMP production.