SMARCA4 inactivating mutations cause concomitant Coffin-Siris syndrome, microphthalmia and small-cell carcinoma of the ovary hypercalcaemic type.
SMARCA4 inactivating mutations cause concomitant Coffin-Siris syndrome, microphthalmia and small-cell carcinoma of the ovary hypercalcaemic type.
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DOI：
10.1002/path.4926
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发表时间：
2017-09
期刊：
影响因子：
--
通讯作者：
Zuffardi O
中科院分区：
文献类型：
--
作者：
Errichiello E;Mustafa N;Vetro A;Notarangelo LD;de Jonge H;Rinaldi B;Vergani D;Giglio SR;Morbini P;Zuffardi O
SMARCA 4染色质重塑因子在11%的Coffin-Siris综合征（CSS）患者和几乎所有卵巢高钙血症型小细胞癌（SCCOHT）肿瘤中发生突变。具有功能获得或显性负效应的错义突变与CSS相关，而导致SMARCA 4表达丧失的失活突变仅见于SCCOHT。我们应用全外显子组测序研究了一名15岁的轻度CSS患者，该患者在13岁时伴随发生SCCOHT。有趣的是，我们的患者还表现出先天性小眼球，这在CSS患者中从未有过报道。我们在SMARCA 4的外显子19中检测到一个从头生殖系杂合无义突变（c.2935C > T;p.Arg979*），在外显子6中检测到一个体细胞移码突变（c.1236_1236delC;p.Gln413Argfs*88），导致肿瘤中SMARCA 4免疫染色完全丧失。免疫组化结果得到以下观察结果的支持：通过逆转录聚合酶链反应检测到c.2935C > T突变体转录物的水平远低于先证者全血和淋巴母细胞系中的野生型等位基因，证实了无义介导的mRNA衰变。因此，免疫印迹证明先证者细胞中SMARCA 4蛋白的量大约是对照组的一半。这项研究表明，与CSS相关的SMARCA 4组成突变不一定是非截短的，并且单倍不足可能解释较温和的CSS表型，如先前报道的单倍不足ARID 1B。此外，我们的病例支持染色质重塑在发育障碍和癌症中的双重作用，以及SMARCA 4参与小眼症，证实了先前在小鼠模型和DECIPHER数据库中的发现。最后，我们推测轻度CSS可能在一部分携带SMARCA 4突变的SCCOHT患者中被低估。© 2017作者。病理学杂志由John Wiley & Sons Ltd代表大不列颠和爱尔兰病理学会出版。
SMARCA4 chromatin remodelling factor is mutated in 11% of Coffin–Siris syndrome (CSS) patients and in almost all small‐cell carcinoma of the ovary hypercalcaemic type (SCCOHT) tumours. Missense mutations with gain‐of‐function or dominant‐negative effects are associated with CSS, whereas inactivating mutations, leading to loss of SMARCA4 expression, have been exclusively found in SCCOHT. We applied whole‐exome sequencing to study a 15‐year‐old patient with mild CSS who concomitantly developed SCCOHT at age 13 years. Interestingly, our patient also showed congenital microphthalmia, which has never previously been reported in CSS patients. We detected a de novo germline heterozygous nonsense mutation in exon 19 of SMARCA4 (c.2935C > T;p.Arg979*), and a somatic frameshift mutation in exon 6 (c.1236_1236delC;p.Gln413Argfs*88), causing complete loss of SMARCA4 immunostaining in the tumour. The immunohistochemical findings are supported by the observation that the c.2935C > T mutant transcript was detected by reverse transcription polymerase chain reaction at a much lower level than the wild‐type allele in whole blood and the lymphoblastoid cell line of the proband, confirming nonsense‐mediated mRNA decay. Accordingly, immunoblotting demonstrated that there was approximately half the amount of SMARCA4 protein in the proband's cells as in controls. This study suggests that SMARCA4 constitutional mutations associated with CSS are not necessarily non‐truncating, and that haploinsufficiency may explain milder CSS phenotypes, as previously reported for haploinsufficient ARID1B. In addition, our case supports the dual role of chromatin remodellers in developmental disorders and cancer, as well as the involvement of SMARCA4 in microphthalmia, confirming previous findings in mouse models and the DECIPHER database. Finally, we speculate that mild CSS might be under‐recognized in a proportion of SCCOHT patients harbouring SMARCA4 mutations. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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影响因子：
29.4
作者：
Tahara T;Yamamoto E;Madireddi P;Suzuki H;Maruyama R;Chung W;Garriga J;Jelinek J;Yamano HO;Sugai T;Kondo Y;Toyota M;Issa JP;Estécio MR
通讯作者：
Estécio MR
影响因子：
5.3
作者：
Bramswig, Nuria C.;Luedecke, Hermann-Josef;Wieczorek, Dagmar
通讯作者：
Wieczorek, Dagmar
影响因子：
9.8
作者：
Weiss, Karin;Terhal, Paulien A.;Muenke, Maximilian
通讯作者：
Muenke, Maximilian
影响因子：
4.7
作者：
Witkowski, Leora;Goudie, Catherine;Foulkes, William D.
通讯作者：
Foulkes, William D.
影响因子：
3.9
作者：
He S;Pirity MK;Wang WL;Wolf L;Chauhan BK;Cveklova K;Tamm ER;Ashery-Padan R;Metzger D;Nakai A;Chambon P;Zavadil J;Cvekl A
通讯作者：
Cvekl A