Crane-Smith, Zoe;
De Castro, Sandra CP;
Nikolopoulou, Evanthia;
Wolujewicz, Paul;
Smedley, Damian;
Lei, Yunping;
Mather, Emma;
... Greene, Nicholas DE; + view all
(2023)
A non-coding insertional mutation of Grhl2 causes gene over-expression and multiple structural anomalies including cleft palate, spina bifida and encephalocele.
Human Molecular Genetics
10.1093/hmg/ddad094.
(In press).
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Abstract
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 hypothesised that regulatory mutations account for a portion of the unidentified heritability. We found that excess expression of Grainyhead-like 2 (Grhl2) not only causes 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, 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 which 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 hypothesise that mutations affecting the regulation of GRHL2 may contribute to craniofacial anomalies and NTDs in humans.
| Type: | Article |
|---|---|
| Title: | A non-coding insertional mutation of Grhl2 causes gene over-expression and multiple structural anomalies including cleft palate, spina bifida and encephalocele |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/hmg/ddad094 |
| Publisher version: | https://doi.org/10.1093/hmg/ddad094 |
| Language: | English |
| Additional information: | Copyright © The Author(s) 2023. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10174221 |
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