Genomic duplication of PTPN11 is an uncommon cause of Noonan syndrome.
Genomic duplication of PTPN11 is an uncommon cause of Noonan syndrome.
复制标题
PTPN11 的基因组重复是努南综合征的一个罕见原因。
DOI：
10.1002/ajmg.a.32992
复制
发表时间：
2009-10
影响因子：
2
通讯作者：
Zenker, Martin
中科院分区：
文献类型：
--
作者：
Graham, John M., Jr.;Kramer, Nancy;Bejjani, Bassem A.;Thiel, Christian T.;Carta, Claudio;Neri, Giovanni;Tartaglia, Marco;Zenker, Martin
关键词：
努南综合征（NS）是一种遗传异质性疾病，最常见的是由PTPN 11中的激活突变引起的。我们报告一个张力减退、发育迟缓的病人，临床表现提示神经性麻痹。高分辨率染色体分析正常，PTPN 11、SOS 1、KRAS、BRAF、RAF 1、MEK和MEK 2的序列分析也正常。阵列CGH显示在12q24.11q24.21（大小为8.98 Mb）处的9个BAC克隆的单拷贝增益，其包括12q24.13处的PTPN 11位点，并通过FISH分析证实。报道了一个类似的病例，并推测这种重复可能占NS病例的15-30%，而在NS基因中没有检测到突变。我们通过定量PCR筛选了250多例已知NS致病基因无突变的NS病例，这些研究均未产生重复范围内的结果。我们还探讨了影响PTPN 11转录物非翻译区（UTR）的从头变化可能代表SHP 2增强表达所涉及的替代事件的可能性。对36名已知基因无突变的NS患者进行DHPLC分析和整个3' UTR直接测序，未显示任何疾病相关变异。这些发现表明PTPN 11的重复是NS的一个不常见的原因，并且该基因的3 'UTR内的功能相关变异似乎在NS中不起主要作用。然而，在PTPN 11基因座重复的个体中反复观察到NS，表明增加剂量的SHP 2可能对细胞内信号传导具有失调作用。
Noonan syndrome (NS) is a genetically heterogeneous disorder caused most commonly by activating mutations in PTPN11. We report a patient with hypotonia, developmental delay and clinical features suggestive of NS. High-resolution chromosome analysis was normal, and sequence analyses of PTPN11, SOS1, KRAS, BRAF, RAF1, MEK, and MEK2 were also normal. Array CGH revealed a single copy gain of 9 BAC clones at 12q24.11q24.21 (8.98 Mb in size), which encompassed the PTPN11 locus at 12q24.13 and was confirmed by FISH analysis. reported a similar case and speculated that such duplications might account for 15–30% of NS cases with no detectable mutation in NS genes. We screened more than 250 NS cases without mutation in known NS disease-causing genes by quantitative PCR, and none of these studies produced results in the duplicated range. We also explored the possibility that de novo changes affecting the untranslated region (UTR) of the PTPN11 transcript might represent an alternative event involved in SHP2 enhanced expression. DHPLC analysis and direct sequencing of the entire 3' UTR in 36 NS patients without mutation in known genes did not show any disease-associated variant. These findings indicate that duplications of PTPN11 represent an uncommon cause of NS, and functionally relevant variations within the 3'UTR of the gene do not appear to play a major role in NS. However, recurrent observations of NS in individuals with duplications involving the PTPN11 locus suggest that increased dosage of SHP2 may have dysregulating effects on intracellular signaling.
登录
查看更多内容
影响因子：
20.3
作者：
Tartaglia, M;Martinelli, S;Biondi, A
通讯作者：
Biondi, A
影响因子：
30.8
作者：
Tartaglia, Marco;Pennacchio, Len A.;Gelb, Bruce D.
通讯作者：
Gelb, Bruce D.
DOI：
10.1002/ajmg.c.30138
发表时间：
2007-08-15
影响因子：
3.1
作者：
Allanson, Judith E.
通讯作者：
Allanson, Judith E.
影响因子：
5.2
作者：
Thiel, CT;Kraus, C;Reis, A
通讯作者：
Reis, A
影响因子：
30.8
作者：
Tartaglia, M;Mehler, EL;Gelb, BD
通讯作者：
Gelb, BD