Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission through four generations.
Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission through four generations.
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DOI：
10.1002/ajmg.a.33342
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发表时间：
2010-04
影响因子：
2
通讯作者：
Lacassie, Yves
中科院分区：
文献类型：
--
作者：
Rauen, Katherine A.;Tidyman, William E.;Estep, Anne L.;Sampath, Srirangan;Peltier, Henry M.;Bale, Sherri J.;Lacassie, Yves
关键词：
皮肤-面部-皮肤（CFC）综合征是RASopathies之一，由蛋白激酶BRAF、MEK 1或MEK 2的杂合性从头突变导致Ras/促分裂原活化蛋白激酶（MAPK）通路活性改变引起。CFC是一种罕见的多发性先天性异常疾病，其中个体具有特征性畸形特征、心脏缺陷、外胚层异常和发育迟缓。我们报告一个7个半月大的男孩与CFC的临床诊断。双向序列分析显示，MEK 2的外显子3中有一个新的c.383C→A的转换，导致一个非同义的错义取代，p.P128Q。其他家庭成员，包括先证者的母亲和同父异母的兄弟姐妹，表现出CFC的表型特征，并对先证者的MEK 2突变进行了筛查。SIFT（从耐受性中分选不耐受性）分析确定新的MEK 2 p.P128Q是有害的。为了证实新突变蛋白的功能改变，使用瞬时转染293 T细胞并随后进行Western分析来证明增加的激酶活性，如通过ERK磷酸化测量的。这是第一个垂直传播的功能性CFC MEK突变的报告病例，进一步扩展了我们对Ras/MAPK通路内生殖系突变的理解。
Cardio-facio-cutaneous (CFC) syndrome is one of the RASopathies and is caused by alteration of activity through the Ras/mitogen-activated protein kinase (MAPK) pathway due to heterozygous de novo mutations in protein kinases BRAF, MEK1 or MEK2. CFC is a rare multiple congenital anomaly disorder in which individuals have characteristic dysmorphic features, cardiac defects, ectodermal anomalies and developmental delay. We report a 7 ½ month-old boy with a clinical diagnosis of CFC. Bidirectional sequence analysis of MEK2 revealed a novel c.383C→A transition in exon 3 resulting in a nonsynonymous missense substitution, p.P128Q. Other family members, including the proband’s mother and half-sibling, displayed phenotypic features of CFC and were also screened for the MEK2 mutation identified in the proband. SIFT (Sorting Intolerant From Tolerant) analysis determined the novel MEK2 p.P128Q to be deleterious. To corroborate the functional alteration of the novel mutant protein, transient transfection of 293T cells with subsequent Western analysis was used to demonstrate increased kinase activity, as measured by ERK phosphorylation. This first reported case of a vertically transmitted functional CFC MEK mutation further expands our understanding of germline mutations within the Ras/MAPK pathway.
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影响因子：
30.8
作者：
Cordeddu, Viviana;Di Schiavi, Elia;Pennacchio, Len A.;Ma'ayan, Avi;Sarkozy, Anna;Fodale, Valentina;Cecchetti, Serena;Cardinale, Alessio;Martin, Joel;Schackwitz, Wendy;Lipzen, Anna;Zampino, Giuseppe;Mazzanti, Laura;Digilio, Maria C.;Martinelli, Simone;Flex, Elisabetta;Lepri, Francesca;Bartholdi, Deborah;Kutsche, Kerstin;Ferrero, Giovanni B.;Anichini, Cecilia;Selicorni, Angelo;Rossi, Cesare;Tenconi, Romano;Zenker, Martin;Merlo, Daniela;Dallapiccola, Bruno;Iyengar, Ravi;Bazzicalupo, Paolo;Gelb, Bruce D.;Tartaglia, Marco
通讯作者：
Tartaglia, Marco
DOI：
10.1126/science.1171396
发表时间：
2009-05-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fan HY;Liu Z;Shimada M;Sterneck E;Johnson PF;Hedrick SM;Richards JS
通讯作者：
Richards JS
影响因子：
13.6
作者：
Li MW;Mruk DD;Cheng CY
通讯作者：
Cheng CY
影响因子：
30.8
作者：
Tartaglia, Marco;Pennacchio, Len A.;Gelb, Bruce D.
通讯作者：
Gelb, Bruce D.
影响因子：
4
作者：
Tidyman, William E.;Rauen, Katherine A.
通讯作者：
Rauen, Katherine A.