Genetic background dependent modifiers of craniosynostosis severity.
Genetic background dependent modifiers of craniosynostosis severity.
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DOI：
10.1016/j.jsb.2020.107629
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发表时间：
2020-12-01
影响因子：
3
通讯作者：
Hatch NE
中科院分区：
文献类型：
--
作者：
Dudakovic A;Nam HK;Wijnen AJV;Hatch NE
具有相同基因突变的患者颅突融合的严重程度各不相同。为了了解这种表型变异的原因，我们将Crouzon综合征的FGFR2+/C342Y小鼠模型回交到C57BL/6和BALB/c的同源背景上。出生后3周，C57BL/6(88%的发病率，P<；.001)突变小鼠可观察到冠状缝融合，而BALB/c FGFR2+/C342Y突变小鼠未观察到冠状缝融合，表明两种模型的表型严重程度不同。为了开始识别先前存在的颅缝融合严重程度的修饰物，我们比较了C57BL/6和BALB/c FGFR2+/+小鼠的颅骨组织的转录组特征。在FGFR2+/C342Y小鼠中，我们分别分析了顶骨冠状缝合组织和矢状缝组织，因为冠状缝合而不是矢状缝融合。与BALB/c相比，与颅缝融合相关的Twist和EN1转录因子在C57BL/6中表达下调，而Runx2表达上调，这可能是颅缝融合的易感性。GO术语MAPK级联下的转录组分析表明，与钙离子通道、血管生成、蛋白质质量控制和细胞应激反应相关的基因是与遗传背景相关的转录组差异的核心。C57BL/6分离的细胞FGFR2和HSPA2蛋白水平及ERK1/2活性高于BALB/c脑组织。值得注意的是，HSPA2蛋白伴侣是颅面遗传上位性的中心，我们发现FGFR2蛋白在FGFR2+/C342Y小鼠的原代细胞中被异常处理，而不是FGFR2+/+小鼠。因此，我们认为蛋白质质量控制反应的差异可能有助于遗传背景对颅缝融合症表型严重性的影响。
Craniosynostosis severity varies in patients with identical genetic mutations. To understand causes of this phenotypic variation, we backcrossed the FGFR2+/C342Y mouse model of Crouzon syndrome onto congenic C57BL/6 and BALB/c backgrounds. Coronal suture fusion was observed in C57BL/6 (88% incidence, p < .001 between genotypes) but not in BALB/c FGFR2+/C342Y mutant mice at 3 weeks after birth, establishing that that the two models differ in phenotype severity. To begin identifying pre-existing modifiers of craniosynostosis severity, we compared transcriptome signatures of cranial tissues from C57BL/6 vs. BALB/c FGFR2+/+ mice. We separately analyzed frontal bone with coronal suture tissue from parietal bone with sagittal suture tissues because the coronal suture but not the sagittal suture fuses in FGFR2+/C342Y mice. The craniosynostosis associated Twist and En1 transcription factors were down-regulated, while Runx2 was up-regulated, in C57BL/6 compared to BALB/c tissues, which could predispose to craniosynostosis. Transcriptome analyses under the GO term MAPK cascade revealed that genes associated with calcium ion channels, angiogenesis, protein quality control and cell stress response were central to transcriptome differences associated with genetic background. FGFR2 and HSPA2 protein levels plus ERK1/2 activity were higher in cells isolated from C57BL/6 than BALB/c cranial tissues. Notably, the HSPA2 protein chaperone is central to craniofacial genetic epistasis, and we find that FGFR2 protein is abnormally processed in primary cells from FGFR2+/C342Y but not FGFR2+/+ mice. Therefore, we propose that differences in protein quality control responses may contribute to genetic background influences on craniosynostosis phenotype severity.
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影响因子：
4.6
作者：
Kawane T;Qin X;Jiang Q;Miyazaki T;Komori H;Yoshida CA;Matsuura-Kawata VKDS;Sakane C;Matsuo Y;Nagai K;Maeno T;Date Y;Nishimura R;Komori T
通讯作者：
Komori T
影响因子：
7
作者：
Ashburner, M;Ball, CA;Yoon, J
通讯作者：
Yoon, J
DOI：
10.1016/j.bbrc.2016.07.111
发表时间：
2016-10-14
影响因子：
3.1
作者：
Chung, Chaeuk;Yoo, Geon;Lee, Jeong Eun
通讯作者：
Lee, Jeong Eun
影响因子：
4.1
作者：
Chen, L;Li, D;Deng, CX
通讯作者：
Deng, CX
影响因子：
4.2
作者：
BELLOWS, CG;AUBIN, JE;ANTOSZ, ME
通讯作者：
ANTOSZ, ME