PTPN11 mutations in Noonan syndrome:: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity
PTPN11 mutations in Noonan syndrome:: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity
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DOI：
10.1086/340847
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发表时间：
2002-06-01
影响因子：
9.8
通讯作者：
Gelb, BD
中科院分区：
文献类型：
--
作者：
Tartaglia, M;Kalidas, K;Gelb, BD
努南综合征（NS）是一种以面部畸形、身材矮小、心脏缺陷和骨骼畸形为特征的发育障碍。我们最近证明了PTPN 11（编码非受体型蛋白酪氨酸磷酸酶SHP-2（src同源区2-结构域磷酸酶-2）的基因）的突变导致NS，在一个小队列中占这种遗传异质性疾病病例的50%。所有突变均为错义突变，并聚集在氨基末端src同源性2（N-SH 2）和蛋白酪氨酸磷酸酶（PTP）结构域的相互作用部分。功能的增强被认为是这种疾病的一种机制。在这里，我们报告了PTPN 11突变的谱和分布在一个大型的，充分表征的NS队列。在119例散发性或家族性NS患者中，54例（45%）发现了突变。有一个显着更高的流行率突变家族性病例比散发。所有缺陷均为错义，有几个是复发性的。绝大多数突变改变了位于N-SH 2和PTP结构域相互作用表面内或周围的氨基酸残基，但缺陷也影响了C-SH 2结构域以及连接N-SH 2和C-SH 2结构域的肽中的残基。基因型-表型分析显示，肺动脉狭窄在有PTPN 11突变的NS受试者组中比在无PTPN 11突变的NS受试者组中更常见（70.6%对46.2%; P < .01），而肥厚型心肌病在有PTPN 11突变的NS受试者中的患病率较低（5.9%对26.2%; P < .005）。其他先天性心脏畸形、身材矮小、胸畸形、隐睾和发育迟缓的患病率在两组之间没有差异。在一个遗传努南样/多发性巨细胞病变综合征的家族中发现了PTPN 11突变，扩展了与该基因相关的疾病表型范围。
Noonan syndrome (NS) is a developmental disorder characterized by facial dysmorphia, short stature, cardiac defects, and skeletal malformations. We recently demonstrated that mutations in PTPN11, the gene encoding the non-receptor-type protein tyrosine phosphatase SHP-2 (src homology region 2-domain phosphatase-2), cause NS, accounting for 50% of cases of this genetically heterogeneous disorder in a small cohort. All mutations were missense changes and clustered at the interacting portions of the amino-terminal src-homology 2 (N-SH2) and protein tyrosine phosphatase (PTP) domains. A gain of function was postulated as a mechanism for the disease. Here, we report the spectrum and distribution of PTPN11 mutations in a large, well-characterized cohort with NS. Mutations were found in 54 of 119 (45%) unrelated individuals with sporadic or familial NS. There was a significantly higher prevalence of mutations among familial cases than among sporadic ones. All defects were missense, and several were recurrent. The vast majority of mutations altered amino acid residues located in or around the interacting surfaces of the N-SH2 and PTP domains, but defects also affected residues in the C-SH2 domain, as well as in the peptide linking the N-SH2 and C-SH2 domains. Genotype-phenotype analysis revealed that pulmonic stenosis was more prevalent among the group of subjects with NS who had PTPN11 mutations than it was in the group without them (70.6% vs. 46.2%; P < .01), whereas hypertrophic cardiomyopathy was less prevalent among those with PTPN11 mutations (5.9% vs. 26.2%; P < .005). The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups. A PTPN11 mutation was identified in a family inheriting Noonan-like/multiple giant-cell lesion syndrome, extending the phenotypic range of disease associated with this gene.