Phosphatase-defective LEOPARD syndrome mutations in PTPN11 gene have gain-of-function effects during Drosophila development
Phosphatase-defective LEOPARD syndrome mutations in PTPN11 gene have gain-of-function effects during Drosophila development
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DOI：
10.1093/hmg/ddn336
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发表时间：
2009-01-01
影响因子：
3.5
通讯作者：
Gelb, Bruce D.
中科院分区：
文献类型：
--
作者：
Oishi, Kimihiko;Zhang, Hui;Gelb, Bruce D.
编码蛋白酪氨酸磷酸酶SHP - 2的PTPN11基因的错义突变会导致临床上相似但有区别的疾病，即豹皮综合征（LEOPARD，LS）和努南综合征（Noonan，NS）。LS是一种常染色体显性遗传病，具有多种发育异常，包括雀斑、心脏缺陷、身材矮小和耳聋。生化分析表明，LS等位基因产生功能丧失（LOF）效应，而NS突变导致功能获得（GOF）。这些生化发现带来了一个谜团，即对功能有相反影响的PTPN11突变如何导致如此相似的疾病。为了研究最常见的LS PTPN11等位基因（Y279C和T468M）对发育的影响，我们利用果蝇中PTPN11的同源基因螺旋（corkscrew，csw）培育了LS转基因果蝇。LS csw突变等位基因的普遍表达导致异位翅脉，并且对于Y279C等位基因，还导致眼睛粗糙且R7光感受器数量增加。这些是由RAS/MAPK信号传导增加介导的GOF表型，并且需要LS突变体的残余磷酸酶活性。我们的研究结果首次提供了证据，表明尽管磷酸酶活性降低，LS突变等位基因仍具有GOF发育效应，这为具有GOF和LOF的PTPN11突变如何产生相似但有区别的综合征提供了理论依据。
Missense mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase SHP-2, cause clinically similar but distinctive disorders, LEOPARD (LS) and Noonan (NS) syndromes. The LS is an autosomal dominant disorder with pleomorphic developmental abnormalities including lentigines, cardiac defects, short stature and deafness. Biochemical analyses indicated that LS alleles engender loss-of-function (LOF) effects, while NS mutations result in gain-of-function (GOF). These biochemical findings lead to an enigma that how PTPN11 mutations with opposite effects on function result in disorders that are so similar. To study the developmental effects of the commonest LS PTPN11 alleles (Y279C and T468M), we generated LS transgenic fruitflies using corkscrew (csw), the Drosophila orthologue of PTPN11. Ubiquitous expression of the LS csw mutant alleles resulted in ectopic wing veins and, for the Y279C allele, rough eyes with increased R7 photoreceptor numbers. These were GOF phenotypes mediated by increased RAS/MAPK signaling and requiring the LS mutant's residual phosphatase activity. Our findings provide the first evidence that LS mutant alleles have GOF developmental effects despite reduced phosphatase activity, providing a rationale for how PTPN11 mutations with GOF and LOF produce similar but distinctive syndromes.