Abstract
Spondylocostal dysostosis (SCD) is an inherited disorder with abnormal vertebral segmentation that results in extensive hemivertebrae, truncal shortening and abnormally aligned ribs. It arises during embryonic development by a disruption of formation of somites (the precursor tissue of the vertebrae, ribs and associated tendons and muscles). Four genes causing a subset of autosomal recessive forms of this disease have been identified: DLL3 (SCDO1: MIM 277300), MESP2 (SCDO2: MIM 608681), LFNG (SCDO3: MIM609813) and HES7 (SCDO4). These genes are all essential components of the Notch signalling pathway, which has multiple roles in development and disease. Previously, only a single SCD-causative missense mutation was described in HES7. In this study, we have identified two new missense mutations in the HES7 gene in a single family, with only individuals carrying both mutant alleles being affected by SCD. In vitro functional analysis revealed that one of the mutant HES7 proteins was unable to repress gene expression by DNA binding or protein heterodimerization.
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Acknowledgements
We thank the family for their cooperation, and Wendy Chua for technical assistance. We are extremely grateful to Ryoichiro Kageyama and Diane Fatkin for providing reagents. This work was funded by National Health and Medical Research Council (NHMRC) Project Grants 404804 and 635500 (SLD and DBS), a Pfizer Foundation Australia Senior Research Fellowship (SLD) and a NHMRC Senior Research Fellowship (SLD). This research was approved by St Vincent's Hospital Human Research Ethics Committee (H05/057), Darlinghurst, Sydney, NSW 2010, Australia.
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Sparrow, D., Sillence, D., Wouters, M. et al. Two novel missense mutations in HAIRY-AND-ENHANCER-OF-SPLIT-7 in a family with spondylocostal dysostosis. Eur J Hum Genet 18, 674–679 (2010). https://doi.org/10.1038/ejhg.2009.241
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DOI: https://doi.org/10.1038/ejhg.2009.241
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