A non-coding insertional mutation of Grhl2 causes gene over-expression and multiple structural anomalies including cleft palate, spina bifida and encephalocele.
A non-coding insertional mutation of Grhl2 causes gene over-expression and multiple structural anomalies including cleft palate, spina bifida and encephalocele.
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DOI：
10.1093/hmg/ddad094
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发表时间：
2023-08-26
影响因子：
3.5
通讯作者：
中科院分区：
文献类型：
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作者：
口面裂，包括唇腭裂（CL/P）和神经管缺陷（NTDs）是最常见的先天性异常，但对这些疾病的遗传基础的了解仍不完整。在CL/P、NTDs和相关异常之间，遗传风险因素共有的程度也不清楚。虽然致病基因的鉴定主要集中在编码和功能突变的丧失上，但假设调节突变占未确定遗传力的一部分。我们发现Grainyhead-like 2 （Grhl2）的过度表达不仅会导致轴向缺陷（Axd）小鼠的脊髓NTDs，还会导致影响颅骨区域的多种附加缺陷。这些包括口面裂，包括中线唇裂和腭裂，以及颅面骨和额部和/或基底脑膨出的异常，其中脑组织通过头盖骨突出或进入鼻腔。为了研究Grhl2Axd菌株的致病突变，全基因组测序发现了一个约4 kb的LTR反转录转座子插入，该插入破坏了位于5 ' UTR上游约300个碱基对的非编码调控区。这种插入也位于预测的长非编码RNA内，它位于反向链上，与Grhl2一样，在Axd （Grhl2Axd）纯合突变胚胎中过度表达。对ntd或腭裂患者GRHL2上游区域的初步分析显示，在少数病例中存在罕见或新颖的变异。我们假设影响GRHL2调控的突变可能导致人类颅面异常和NTDs。
Orofacial clefts, including cleft lip and palate (CL/P) and neural tube defects (NTDs) are among the most common congenital anomalies, but knowledge of the genetic basis of these conditions remains incomplete. The extent to which genetic risk factors are shared between CL/P, NTDs and related anomalies is also unclear. While identification of causative genes has largely focused on coding and loss of function mutations, it is hypothesized that regulatory mutations account for a portion of the unidentified heritability. We found that excess expression of Grainyhead-like 2 (Grhl2) causes not only spinal NTDs in Axial defects (Axd) mice but also multiple additional defects affecting the cranial region. These include orofacial clefts comprising midline cleft lip and palate and abnormalities of the craniofacial bones and frontal and/or basal encephalocele, in which brain tissue herniates through the cranium or into the nasal cavity. To investigate the causative mutation in the Grhl2Axd strain, whole genome sequencing identified an approximately 4 kb LTR retrotransposon insertion that disrupts the non-coding regulatory region, lying approximately 300 base pairs upstream of the 5’ UTR. This insertion also lies within a predicted long non-coding RNA, oriented on the reverse strand, which like Grhl2 is over-expressed in Axd (Grhl2Axd) homozygous mutant embryos. Initial analysis of the GRHL2 upstream region in individuals with NTDs or cleft palate revealed rare or novel variants in a small number of cases. We hypothesize that mutations affecting the regulation of GRHL2 may contribute to craniofacial anomalies and NTDs in humans.
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影响因子：
14.9
作者：
Baldarelli RM;Smith CM;Finger JH;Hayamizu TF;McCright IJ;Xu J;Shaw DR;Beal JS;Blodgett O;Campbell J;Corbani LE;Frost PJ;Giannatto SC;Miers DB;Kadin JA;Richardson JE;Ringwald M
通讯作者：
Ringwald M
DOI：
10.1038/nrdp.2015.7
发表时间：
2015-04-30
期刊：
Nature reviews. Disease primers
影响因子：
--
作者：
Copp AJ;Adzick NS;Chitty LS;Fletcher JM;Holmbeck GN;Shaw GM
通讯作者：
Shaw GM
影响因子：
2.7
作者：
de Vries M;Carpinelli M;Rutland E;Hatzipantelis A;Partridge D;Auden A;Anderson PJ;De Groef B;Wu H;Osterwalder M;Visel A;Jane SM;Dworkin S
通讯作者：
Dworkin S
影响因子：
4.9
作者：
Elmer JL;Hay AD;Kessler NJ;Bertozzi TM;Ainscough EAC;Ferguson-Smith AC
通讯作者：
Ferguson-Smith AC
DOI：
10.1007/s00381-023-05883-7
发表时间：
2023-07
期刊：
Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery
影响因子：
--
作者：
Vakharia VN;Toescu S;Copp AJ;Thompson DNP
通讯作者：
Thompson DNP