Short Stature is Progressive in Patients with Heterozygous NPR2 Mutations
Short Stature is Progressive in Patients with Heterozygous NPR2 Mutations
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DOI：
10.1210/clinem/dgaa491
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发表时间：
2020-10-01
影响因子：
5.8
通讯作者：
Levine, Michael A.
中科院分区：
文献类型：
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作者：
Hanley, Patrick C.;Kanwar, Harsh S.;Levine, Michael A.
背景：NPR2编码心钠素受体B(ANPRB)，它是一种骨骼生长调节因子。目的：描述一个具有新的NPR2基因突变的大家族成员的身体比例和生长特征。设计和参与者：我们对2名健康父母和2名患有AMDM的儿童进行了外显子全基因组测序。在一个学术医学中心，对一个多代家庭的成员进行了详细的基因分型和表型分析。结果：AMDM姐妹是NPR2基因错义突变的复合杂合子，一个新的p.P93S(母系)和一个已报道的p.R989L(父系)。两种突变型ANPRB蛋白均在HEK293T细胞中正常表达，并对野生型ANPRB的催化活性表现出明显的负效应。与野生型亲属(-1.37+/-0.59)相比，杂合子亲属的身高(身高z分数-2.06+/-0.97，中位数+/-SD)成比例的矮小。结论：双等位基因NPR2突变可导致严重的骨骼发育不良(AMDM)，而杂合突变可导致以进行性矮小为特征的微妙表型，其特征是随年龄增加身高潜力丧失。
Background: NPR2 encodes atrial natriuretic peptide receptor B (ANPRB), a regulator of skeletal growth. Biallelic loss-of-function mutations in NPR2 result in acromesomelic dysplasia Maroteaux type (AMDM; OMIM 602875), while heterozygous mutations may account for 2% to 6% of idiopathic short stature (ISS).Objective: Describe the physical proportions and growth characteristics of an extended family with novel NPR2 mutations including members with AMDM, ISS, or normal stature.Design and Participants: We performed whole exome sequencing in 2 healthy parents and 2 children with AMDM. Detailed genotyping and phenotyping were performed on members of a multigenerational family in an academic medical center. We expressed mutant proteins in mammalian cells and characterized expression and function.Results: The sisters with AMDM were compound heterozygotes for missense mutations in the NPR2 gene, a novel p.P93S (maternal) and the previously reported p.R989L (paternal). Both mutant ANPRB proteins were normally expressed in HEK293T cells and exhibited dominant negative effects on wild-type ANPRB catalytic activity. Heterozygous relatives had proportionate short stature (height z-scores -2.06 +/- 0.97, median +/- SD) compared with their wild-type siblings (-1.37 +/- 0.59). Height z-scores progressively and significantly decreased as NPR2-heterozygous children matured, while remaining constant in their wild-type siblings.Conclusions: Biallelic NPR2 mutations cause severe skeletal dysplasia (AMDM), whereas heterozygous mutations lead to a subtler phenotype characterized by progressive short stature with by increasing loss of height potential with age.