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51.
A Novel ZRS Mutation Leads to Preaxial Polydactyly Type 2 in a Heterozygous Form and Werner Mesomelic Syndrome in a Homozygous Form 下载免费PDF全文
Yuan Xue Donna Daentl Ethylin Wang Jabs William R. Wilcox Nadav Ahituv 《Human mutation》2014,35(8):945-948
Point mutations in the zone of polarizing activity regulatory sequence (ZRS) are known to cause human limb malformations. Although most mutations cause preaxial polydactyly (PPD), triphalangeal thumb (TPT) or both, a mutation in position 404 of the ZRS causes more severe Werner mesomelic syndrome (WMS) for which malformations include the distal arm or leg bones in addition to the hands and/or feet. Of more than 15 reported families with ZRS mutations, only one homozygous individual has been reported, with no change in phenotype compared with heterozygotes. Here, we describe a novel point mutation in the ZRS, 402C>T (AC007097.4:g.105548C>T), that is transmitted through two Mexican families with one homozygous individual. The homozygous phenotype for this mutation, WMS, is more severe than the numerous heterozygous individuals genotyped from both families who have TPT and PPD. A mouse transgenic enhancer assay shows that this mutation causes an expansion of the enhancer's expression domain in the developing mouse limb, confirming its pathogenicity. Combined, our results identify a novel ZRS mutation in the Mexican population, 402C>T, and suggest that a dosage effect exists for this ZRS mutation. 相似文献
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在肢体发育中,Sonic hedgehog(SHH)蛋白作为极化区(the zone of polarizing actiVity,ZPA)的调节因子,发挥着十分重要的作用。然而SHH是如何沿着肢体的前后轴发挥调控作用的还不是很清楚。最近的报道表明SHH主要是通过阻止转录因子GLI3裂解成抑制形式发挥作用,而后者也能够关闭SHH靶基因的表达。GLI基因家族的成员编码含有锌指结构的转录因子,主要对SHH的靶基因发挥调节作用。现就GLI基因在肢体发育中的表达特点及其临床意义进行综述。 相似文献
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MiR-21/Sonic Hedgehog (SHH)/PI3K/AKT Pathway is Associated with NSCLC of Primary EGFR-TKI Resistance
Li Xu Kang Li Jia Li Liyu Liu Fang Xu Yan Xu Yi Kong Xingxiang Pu Qianzhi Wang Jingyi Wang Bolin Chen Lin Wu 《Oncologie》2022,24(3):579-590
Background: Non-small cell lung cancer (NSCLC), caused by abnormal gene drive, may have primary drug resistance after treatment with tyrosine kinase inhibitors (EGFR-TKIs). Therefore, we explore whether the primary
drug-resistant NSCLC treated with EGFR-TKI is related to the miR-21/Sonic Hedgehog (SHH)/PI3K/AKT pathway. Methods: The patients from our hospital who meet the AJCC TNM staging (7th edition) stage IIIB and stage
IV NSCLC were selected in this case study. Thereafter, the treatment response of EGFR-TKIs was evaluated
according to the solid tumor efficacy evaluation standard (version 1.1). The patients were divided into the
EGFR-TKIs primary drug resistance group (EGFR-TKIs-Primary-R) and the EGFR-TKIs sensitive group
(EGFR-TKIs-Primary-S). Apoptosis level and degree of fibrosis in patients’ tumor tissues were detected by the
TUNEL assay and Masson staining, respectively. The levels of miR-21 and GLI1 were measured by qRT-PCR
technique. The contents of E-cadherin and Snail were detected by IF method, and the degree of PI3K/AKT phosphorylation was measured using IHC technique. Results: Compared with the EGFR-TKIs-Primary-S group, the
EGFR-TKIs-Primary-R group showed lower levels of apoptosis and tumor tissue fibrosis. The levels of miR-21,
GLI1, Snail, p-PI3K and p-AKT increased, while the level of E-cadherin decreased. However, the levels of total
protein PI3K and AKT remained the same. Conclusion: NSCLC of primary EGFR-TKI resistance was found
to be related to miR-21/SHH, the process of epithelial to mesenchymal transition (EMT), and PI3K/AKT phosphorylation. The present study provides a reference for future research in drug resistance, and paves the way to
discover new therapeutic gene targets to alleviate lung cancer drug resistance. 相似文献
55.
目的检测Hedgehog信号通路中SHH蛋白及其下游转录因子GLI1蛋白在人Peutz-Jeghers综合征(PJS)息肉中的表达,探讨其在PJS发生及恶变中的作用。方法采用免疫组织化学方法检测PJS息肉(20例)、正常肠黏膜组织(20例)、大肠腺瘤性息肉(25例)、大肠腺癌(25例)组织中SHH和GLI1蛋白的表达和分布,并比较表达程度的差异。结果免疫组织化学检测SHH蛋白和GLI1蛋白的阳性着色主要分布于胞膜和胞质,腺癌中GLI1蛋白的胞质和核染色增加。SHH蛋白和GLI1蛋白在正常肠黏膜组织、PJS息肉组织、腺瘤组织及腺癌组织中的阳性表达率和表达强度依次增高,差异具有统计学意义(Kruskal-Wallis H test,P<0.001)。SHH与GLI1的蛋白表达在PJS中经Spearman等级相关分析呈正相关(rp=0.503,P=0.024)。结论 SHH/GLI1在正常肠黏膜组织、PJS息肉组织、腺瘤组织及腺癌组织中均有表达,且表达水平依次增高,提示SHH-GLI1信号通路可能与PJS息肉的发生及恶变有关。 相似文献
56.
Bertolacini CD Ribeiro-Bicudo LA Petrin A Richieri-Costa A Murray JC 《Clinical genetics》2012,81(1):70-75
Mutations in the human GLI2 gene were first reported in association with defective anterior pituitary formation, panhypopituitarism, and forebrain anomalies represented by typical holoprosencephaly (HPE) and holoprosencephaly-like (HPE-L) phenotypes and postaxial polydactyly. Subsequently, anophthalmia plus orbital anomalies, heminasal aplasia, branchial arch anomalies and polydactyly have also been incorporated into the general phenotype. Here we described six Brazilian patients with phenotypic manifestations that range from isolated cleft lip/palate with polydactyly, branchial arch anomalies to semi-lobar holoprosencephaly. Novel sequence variants were found in the GLI2 gene in patients with marked involvement of the temporomandibular joint (TMJ), a new clinical finding observed with mutations of this gene. Clinical, molecular and genetic aspects are discussed. 相似文献
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