An Exploration of Mutagenesis in a Family with Cleidocranial Dysplasia without RUNX2 Mutation.
An Exploration of Mutagenesis in a Family with Cleidocranial Dysplasia without RUNX2 Mutation.
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无RUNX2突变的锁骨颅骨发育不良家系的诱变探索
DOI：
10.3389/fgene.2021.748111
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发表时间：
2021
影响因子：
3.7
通讯作者：
Zheng S
中科院分区：
文献类型：
--
作者：
Liu D;Liu Y;Zhang X;Wang Y;Zhang C;Zheng S
锁骨颅骨发育不全（CCD）是一种常染色体显性遗传性骨骼疾病，其特征为颅骨发育不良、锁骨发育不全和牙齿异常。涉及Runt相关转录因子2（RUNX2）的突变是目前已知的CCD唯一分子病因，但并非在所有CCD患者中都能检测到。约20 - 30%的患者无法检测到RUNX2异常，其分子病因仍不清楚。本研究包括一个具有CCD典型特征的家族病例。首先通过测序分析筛查RUNX2突变，未检测到突变。然后通过定量PCR和多重连接依赖探针扩增（MLPA）检测RUNX2基因的拷贝数变化，未检测到RUNX2的拷贝数变异。我们进行了全外显子组测序（WES）以确定潜在的基因突变。出乎意料的是，在与RUNX2信号通路相关的基因中未检测到异常。因此，推测其他新的未知基因变异可能导致CCD表型。我们关注免疫球蛋白超家族成员10（IGSF10），一个与骨骼发育相关的基因。通过WES检测到一个IGSF10移码突变（c.6001_6002delCT，p.Leu2001Valfs*24）。桑格测序验证该突变仅在患者及其患病母亲中检测到，而在未患病的父亲中未检测到。生物信息学研究表明，该突变可改变IGSF10蛋白的三维结构并严重损害其功能。此外，与正常对照相比，IGSF10基因敲低抑制了碱性磷酸酶（ALP）活性和形成矿化结节的能力。IGSF10基因敲低显著降低了骨涎蛋白（BSP）的表达，但不影响其他成骨标志物的表达。我们的结果提供了新的遗传学证据，表明IGSF10突变可能导致CCD。
Cleidocranial dysplasia (CCD) is an autosomal dominant inheritable skeletal disorder characterized by cranial dysplasia, clavicle hypoplasia, and dental abnormalities. Mutations involving Runt-related transcription factor 2 (RUNX2) are currently the only known molecular etiology for CCD but are not identified in all CCD patients. No RUNX2 abnormality can be detected in about 20–30% of patients, and the molecular cause remains unknown. The present study includes a family case with typical features of CCD. RUNX2 mutation was first screened by sequencing analysis, and no mutation was detected. Copy number alterations of the RUNX2 gene were then measured by quantitative PCR and multiplex ligation-dependent probe amplification (MLPA). No copy number variation in RUNX2 could be detected. We performed whole-exome sequencing (WES) to identify the underlying genetic mutations. Unexpectedly, no abnormalities could be detected in genes related to the RUNX2 signaling pathway. Therefore, it was supposed that other new unknown gene variations might contribute to the CCD phenotype. We focused on Immunoglobulin superfamily member 10 (IGSF10), a gene related to bone development. An IGSF10 frameshift mutation (c.6001_6002delCT, p.Leu2001Valfs*24) was detected by WES. Sanger sequencing verified that this mutation was only detected in the patient and her affected mother but not in her unaffected father. Bioinformatics studies demonstrated that this mutation could change the 3D structure of the IGSF10 protein and severely damage its function. In addition, alkaline phosphatase (ALP) activity and the ability to form mineralized nodules were inhibited by IGSF10 knockdown compared with normal controls. The expression of bone sialoprotein (BSP) was significantly reduced by IGSF10 knockdown, but not that of other osteogenic markers. Our results provide new genetic evidence that IGSF10 mutation might contribute to CCD.
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影响因子：
2.9
作者：
Hintzsche JD;Robinson WA;Tan AC
通讯作者：
Tan AC
影响因子：
5.8
作者：
Lima Amato, Lorena Guimaraes;Montenegro, Luciana Ribeiro;Gontijo Silveira, Leticia Ferreira
通讯作者：
Gontijo Silveira, Leticia Ferreira
影响因子：
2
作者：
Garavelli, L.;D'Apice, M. R.;Novelli, G.
通讯作者：
Novelli, G.
DOI：
10.1007/s11568-008-9024-y
发表时间：
2008-01-01
期刊：
Genomic medicine
影响因子：
--
作者：
Lee, Ming Ta Michael;Tsai, Anne Chun-Hui;Tsai, Fuu-Jen
通讯作者：
Tsai, Fuu-Jen
影响因子：
9.8
作者：
Mendoza-Londono, R;Lammer, E;Lee, B
通讯作者：
Lee, B