Mutations in NOTCH2 in patients with Hajdu-Cheney syndrome.
Mutations in NOTCH2 in patients with Hajdu-Cheney syndrome.
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Hajdu-Cheney综合征患者Notch2突变。
DOI：
10.1007/s00198-013-2298-5
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发表时间：
2013-08
影响因子：
4
通讯作者：
Mannstadt, M.
中科院分区：
文献类型：
--
作者：
Zhao, W.;Petit, E.;Gafni, R. I.;Collins, M. T.;Robey, P. G.;Seton, M.;Miller, K. K.;Mannstadt, M.
Hajdu-Cheney综合征是一种非常罕见的疾病，影响多个器官系统，导致严重的骨质疏松症和其他异常。我们描述了9例这种疾病的临床和遗传学研究结果。Hajdu-Cheney综合征（HCS）是一种罕见的常染色体显性遗传疾病，其特征是严重的骨质疏松症，远端指骨的肢端骨质溶解，肾囊肿和其他异常。最近，NOTCH 2的杂合突变被确定为HCS的原因。9例HCS典型表现的患者参加了这项研究：5例受影响的患者来自两个小家庭和4例散发病例。在每个家庭的一个受影响的个体和所有四个散发病例中获得外周血DNA并进行外显子组测序。桑格测序证实了所有患者的突变。将鉴定的突变之一引入编码NOTCH 2的质粒中。在HEK 293细胞中瞬时表达野生型和突变型N 0 TCH 2以评估配体活化后的细胞内定位。在所有患者中均发现了最后一个NOTCH 2外显子的有害杂合突变; 6个突变中有5个是新突变。与之前的报道一致，预计所有突变都会导致脯氨酸/谷氨酸/丝氨酸/苏氨酸序列的丢失，该序列携带降解信号，因此表明存在激活突变。6个突变中的一个进一步预测了NOTCH 2的第二核定位信号的破坏，但是该突变体在转染后显示正常的核定位，这与所提出的作为该常染色体显性疾病的原因的功能获得机制一致。我们的研究结果证实，杂合NOTCH 2突变是HCS的原因，并扩大了这种疾病的突变谱。
The Hajdu–Cheney syndrome is a very rare disease that affects several organ system, leading to severe osteoporosis and other abnormalities. We describe clinical and genetic findings of nine patients with this disease. The Hajdu–Cheney syndrome (HCS) is a rare autosomal dominant disorder characterized by severe osteoporosis, acroosteolysis of the distal phalanges, renal cysts, and other abnormalities. Recently, heterozygous mutations in NOTCH2 were identified as the cause of HCS. Nine patients with typical presentations of HCS took part in this study: five affected patients from two small families and four sporadic cases. Peripheral blood DNA was obtained and exome sequencing performed in one affected individual per family and in all four sporadic cases. Sanger sequencing confirmed mutations in all patients. One of the identified mutations was introduced in a plasmid encoding NOTCH2. Wild-type and mutant NOTCH2 were transiently expressed in HEK293 cells to assess intracellular localization after ligand activation. Deleterious heterozygous mutations in the last NOTCH2 exon were identified in all patients; five of the six mutations were novel. Consistent with previous reports, all mutations are predicted to result in a loss of the proline/glutamic acid/serine/threonine sequence, which harbors signals for degradation, therefore suggesting activating mutations. One of the six mutations furthermore predicted disruption of the second nuclear localization signal of NOTCH2, but the mutant revealed normal nuclear localization after transfection, which is consistent with the proposed gain-of-function mechanism as the cause of this autosomal dominant disease. Our findings confirm that heterozygous NOTCH2 mutations are the cause of HCS and expand the mutational spectrum of this disorder.
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影响因子：
2.6
作者：
HAJDU, N;KAUNTZE, R
通讯作者：
KAUNTZE, R
影响因子：
3.9
作者：
Majewski, Jacek;Schwartzentruber, Jeremy A.;Samuels, Mark E.
通讯作者：
Samuels, Mark E.
影响因子：
56.9
作者：
ROGERS, S;WELLS, R;RECHSTEINER, M
通讯作者：
RECHSTEINER, M
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
5.2
作者：
Gray, Mary J.;Kim, Chong Ae;Robertson, Stephen P.
通讯作者：
Robertson, Stephen P.