Identification of ENPP1 Haploinsufficiency in Patients With Diffuse Idiopathic Skeletal Hyperostosis and Early-Onset Osteoporosis.
Identification of ENPP1 Haploinsufficiency in Patients With Diffuse Idiopathic Skeletal Hyperostosis and Early-Onset Osteoporosis.
复制标题
DOI：
10.1002/jbmr.4550
复制
发表时间：
2022-06
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
纯合子ENPP 1突变与常染色体隐性遗传性低磷血症佝偻病2型（ARHR 2）、脊柱韧带严重骨化和婴儿1型全身动脉钙化相关。关于与杂合ENPP 1突变相关的表型的报道数量有限。在这里，我们报告了一系列的三个先证者和他们的家庭与杂合子和复合杂合子ENPP 1突变。第1例（病例1）是一名47岁男性，诊断为早发性骨质疏松症，血清磷酸盐水平低于正常值，怀疑为低磷酸盐血症性佝偻病。第二例和第三例分别为77岁和54岁的女性，均表现为严重的脊柱韧带骨化和弥漫性特发性骨肥厚（DISH）的推定诊断。在检查时，发现病例2中的成纤维细胞生长因子23（FGF 23）相对较高，病例3中的血清磷水平较低-正常，并考虑诊断为X连锁低磷血症性佝偻病（XLH）和ARHR 2。因此，对与先天性低磷血症佝偻病相关的基因进行了遗传检测，在病例1和2中发现了杂合ENPP 1变体第1例，c.536A>G，p.Asn179Ser;病例2，c.1352A>G，p.Tyr451Cys），以及构成病例1和2中存在的相同变体的病例3中的复合杂合ENPP 1变体（c.536A>G，p.Asn179Ser和c.1352A>G，p.Tyr451Cys）。几种计算机模拟工具预测这两种变体是致病性的，体外生化分析证实了这一发现，表明p.Asn179Ser和p.Tyr451Cys ENPP 1变体的催化速度分别为野生型ENPP 1的45%和30%。因此，这两种变体均被归类为致病性功能丧失突变。我们的研究结果表明，ENPP 1突变状态应评估诊断为特发性DISH，骨化的后纵韧带（OPLL），早发性骨质疏松症的患者。
Homozygous ENPP1 mutations are associated with autosomal recessive hypophosphatemic rickets type 2 (ARHR2), severe ossification of the spinal ligaments, and generalized arterial calcification of infancy type 1. There are a limited number of reports on phenotypes associated with heterozygous ENPP1 mutations. Here, we report a series of three probands and their families with heterozygous and compound heterozygous ENPP1 mutations. The first case (case 1) was a 47-year-old male, diagnosed with early-onset osteoporosis and low-normal serum phosphate levels, which invoked suspicion for hypophosphatemic rickets. The second and third cases were 77 and 54 year-old females who both presented with severe spinal ligament ossification and the presumptive diagnosis of diffuse idiopathic skeletal hyperostosis (DISH). Upon work up, fibroblast growth factor 23 (FGF23) was noted to be relatively high in case 2 and serum phosphorous was low-normal in case 3, and the diagnoses of X-linked hypophosphatemic rickets (XLH) and ARHR2 were considered. Genetic testing for genes related to congenital hypophosphatemic rickets was therefore performed, revealing heterozygous ENPP1 variants in cases 1 and 2 (case 1, c.536A>G, p.Asn179Ser; case 2, c.1352A>G, p.Tyr451Cys), and compound heterozygous ENPP1 variants in case 3 constituting the same variants present in cases 1 and 2 (c.536A>G, p.Asn179Ser and c.1352A>G, p.Tyr451Cys). Several in silico tools predicted the two variants to be pathogeneic, a finding confirmed by in vitro biochemical analysis demonstrating that the p.Asn179Ser and p.Tyr451Cys ENPP1 variants possessed a catalytic velocity of 45% and 30% compared to that of wild type ENPP1, respectively. Both variants were therefore categorized as pathogenic loss-of-function mutations. Our findings suggest that ENPP1 mutational status should be evaluated in patients presenting with the diagnosis of idiopathic DISH, ossification of the posterior longitudinal ligament (OPLL), and early-onset osteoporosis.
登录
查看更多内容
DOI：
10.1002/jbmr.3938
发表时间：
2020-04
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
--
作者：
Kotwal A;Ferrer A;Kumar R;Singh RJ;Murthy V;Schultz-Rogers L;Zimmermann M;Lanpher B;Zimmerman K;Stabach PR;Klee E;Braddock DT;Wermers RA
通讯作者：
Wermers RA
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：
2.4
作者：
Kawaguchi, Yoshiharu;Kitajima, Isao;Kimura, Tomoatsu
通讯作者：
Kimura, Tomoatsu
影响因子：
6.2
作者：
Carpenter, Thomas O.;Imel, Erik A.;Holm, Ingrid A.;de Beur, Suzanne M. Jan;Insogna, Karl L.
通讯作者：
Insogna, Karl L.
影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.