Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.
Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.
复制标题
DOI：
10.1002/ajmg.a.36863
复制
发表时间：
2015-03
期刊：
影响因子：
--
通讯作者：
Sol-Church K
中科院分区：
文献类型：
--
作者：
Gripp KW;Robbins KM;Sobreira NL;Witmer PD;Bird LM;Avela K;Makitie O;Alves D;Hogue JS;Zackai EH;Doheny KF;Stabley DL;Sol-Church K
外侧脑膜膨出综合征(LMS，OMIM%130720)，又称雷曼综合征，是一种非常罕见的骨骼疾病，伴有面部畸形、低眼压和脑膜膨出相关的神经功能障碍。特征性的侧方脑膜膨出是硬脑膜扩张症的严重末端，通常在下脊柱最为严重。LMS的面部特征包括端头过长和远距花纹、高拱眉、上睑下垂、面中部发育不良、小颌下垂、腭部高而窄、耳朵低垂和低张外观。过度伸展、疝气和脊柱侧弯反映结缔组织异常，可能出现主动脉扩张、高音鼻音、蠕虫状骨质和骨溶解。侧方脑膜膨出综合征与Hajdu-Cheney综合征有表型重叠。我们对5名无血缘关系的LMS患者进行了外显子组重测序，发现NOTCH3突变杂合子截断。在另一个无关的个体中，桑格测序发现了同一外显子33中的一个有害变异。总体而言，在6名无关患者中发现了5个新的从头NOTCH3突变。其中1例为26bp缺失(c.6461_6486del，p.G2154fsTer78)，2例为相同的单碱基插入(c.6692_93insC，p.P2231fsTer11)，3例为c.6247A>；T(pK2083*)、c.6663C>；G(p.Y2221*)或c.6732C>；A(p.Y2244*)的无义突变。所有突变都聚集到最后一个编码外显子，导致蛋白质提前终止，并截断富含脯氨酸-谷氨酸-丝氨酸-苏氨酸的负调控结构域。我们的结果表明，突变的信使核糖核酸产物逃脱了无意义介导的腐烂。截短的NOTCH3可能通过减少活性细胞内产物的清除而导致功能获得，类似于临床相关Hajdu-Cheney综合征中的NOTCH2突变，并与导致CADASIL的NOTCH3错义突变形成对比。
Lateral meningocele syndrome (LMS, OMIM%130720), also known as Lehman syndrome, is a very rare skeletal disorder with facial anomalies, hypotonia and meningocele-related neurologic dysfunction. The characteristic lateral meningoceles represent the severe end of the dural ectasia spectrum and are typically most severe in the lower spine. Facial features of LMS include hypertelorism and telecanthus, high arched eyebrows, ptosis, midfacial hypoplasia, micrognathia, high and narrow palate, low-set ears and a hypotonic appearance. Hyperextensibility, hernias and scoliosis reflect a connective tissue abnormality, and aortic dilation, a high-pitched nasal voice, wormian bones and osteolysis may be present. Lateral meningocele syndrome has phenotypic overlap with Hajdu–Cheney syndrome. We performed exome resequencing in five unrelated individuals with LMS and identified heterozygous truncating NOTCH3 mutations. In an additional unrelated individual Sanger sequencing revealed a deleterious variant in the same exon 33. In total, five novel de novo NOTCH3 mutations were identified in six unrelated patients. One had a 26 bp deletion (c.6461_6486del, p.G2154fsTer78), two carried the same single base pair insertion (c.6692_93insC, p.P2231fsTer11), and three individuals had a nonsense point mutation at c.6247A > T (pK2083*), c.6663C>G (p.Y2221*) or c.6732C >A, (p. Y2244*). All mutations cluster into the last coding exon, resulting in premature termination of the protein and truncation of the negative regulatory proline-glutamate-serine-threonine rich PEST domain. Our results suggest that mutant mRNA products escape nonsense mediated decay. The truncated NOTCH3 may cause gain-of-function through decreased clearance of the active intracellular product, resembling NOTCH2 mutations in the clinically related Hajdu–Cheney syndrome and contrasting the NOTCH3 missense mutations causing CADASIL.
登录
查看更多内容
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
2
作者：
Castori, Marco;Morlino, Silvia;Grammatico, Paola
通讯作者：
Grammatico, Paola
影响因子：
6.2
作者：
Tao, Jianning;Chen, Shan;Yang, Tao;Dawson, Brian;Munivez, Elda;Bertin, Terry;Lee, Brendan
通讯作者：
Lee, Brendan
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
9.8
作者：
Martignetti, John A.;Tian, Lifeng;Hakonarson, Hakon
通讯作者：
Hakonarson, Hakon