Cognitive Profile of Disorders Associated With Dysregulation of the RAS/MAPK Signaling Cascade
Cognitive Profile of Disorders Associated With Dysregulation of the RAS/MAPK Signaling Cascade
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DOI：
10.1002/ajmg.a.32488
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发表时间：
2009-02-01
影响因子：
2
通讯作者：
Zampino, Giuseppe
中科院分区：
文献类型：
--
作者：
Cesarini, Laura;Alfieri, Paolo;Zampino, Giuseppe
参与RAS/MAPK通路的转导基因的突变被认为是导致一组具有不同严重程度的认知缺陷的临床相关发育障碍的分子原因。为了确定与这一信号级联失调相关的认知缺陷的频谱，我们研究了PTPN11、SOS1、HRAS、KRAS、BRAF、RAF1和MEK1基因突变患者的认知能力谱以及表型-基因型相关性。我们的发现支持了这样的观察，即认知能力的异质性至少可以部分归因于个体受影响的基因和所涉及的突变类型。虽然影响RAS上游转导的突变较少与智力低下有关，但该通路下游部分的突变通常与更严重的认知障碍有关。在PTPN11杂合突变的患者中，与携带N308D突变的个体相比，T468M替换与平均智商显著升高相关。我们的研究提供了对RAS信号异常的基因突变患者的认知能力范围的见解，表明认知参与的存在和严重程度可以部分地由所涉及的基因来预测。(C)2009年Wiley-Liss，Inc.
Mutations in genes coding for transducers participating in the RAS/MAPK pathway have been identified as the molecular cause underlying a group of clinically related developmental disorders with cognitive deficits of variable severity. To determine the spectrum of cognitive defects associated with dysregulation of this signal cascade, we studied the profile of cognitive abilities in patients with mutations affecting the PTPN11, SOS1, HRAS, KRAS, BRAF, RAF1, and MEK1 genes and phenotype-genotype correlations. Our findings support the observation that heterogeneity in cognitive abilities can be at least partially ascribed to the individual affected genes and type of mutation involved. While mutations affecting transducers upstream of RAS were less frequently associated with mental retardation, mutations in downstream components of the pathway were generally associated with a more severe cognitive impairment. Among patients with a heterozygous PTPN11 mutation, the T468M substitution was associated with a mean IQ significantly higher compared to that of individuals carrying the N308D change. Our study provides insights on the range of cognitive abilities in patients with gene mutations causing dysregulation of RAS signaling suggesting that the presence and severity of cognitive involvement can be predicted in part by the gene involved. (c) 2009 Wiley-Liss, Inc.