Jacob W P Potuijt1, Martijn Baas2, Rivka Sukenik-Halevy3,4,5, Hannie Douben6, Picard Nguyen2, Deon J Venter7,8,9, Renée Gallagher7, Sigrid M Swagemakers10,11, Steven E R Hovius2, Christianne A van Nieuwenhoven2, Robert-Jan H Galjaard6, Peter J van der Spek10,11, Nadav Ahituv3,4, Annelies de Klein6. 1. Department of Plastic and Reconstructive Surgery and Hand Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. j.potuijt@erasmusmc.nl. 2. Department of Plastic and Reconstructive Surgery and Hand Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 3. Department of Bioengineering and Therapeutic Sciences, University of California-San Francisco, San Francisco, California, USA. 4. Institute for Human Genetics, University of California-San Francisco, San Francisco, California, USA. 5. Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel. 6. Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 7. Department of Pathology, Mater Health Services, South Brisbane, Queensland, Australia. 8. Department of Neuropathology, Royal Prince Alfred Hospital, Camperdown, Sydney, Australia. 9. School of Medicine, University of Wollongong, Wollongong, New South Wales, Australia. 10. Department of Bioinformatics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 11. Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Abstract
PURPOSE: The zone of polarizing activity regulatory sequence (ZRS) is an enhancer that regulates sonic hedgehog during embryonic limb development. Recently, mutations in a noncoding evolutionary conserved sequence 500 bp upstream of the ZRS, termed the pre-ZRS (pZRS), have been associated with polydactyly in dogs and humans. Here, we report the first case of triphalangeal thumb-polysyndactyly syndrome (TPT-PS) to be associated with mutations in this region and show via mouse enhancer assays how this mutation leads to ectopic expression throughout the developing limb bud. METHODS: We used linkage analysis, whole-exome sequencing, Sanger sequencing, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, single-nucleotide polymorphism array, and a mouse transgenic enhancer assay. RESULTS: Ten members of a TPT-PS family were included in this study. The mutation was linked to chromosome 7q36 (LOD score 3.0). No aberrations in the ZRS could be identified. A point mutation in the pZRS (chr7:156585476G>C; GRCh37/hg19) was detected in all affected family members. Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud (E11.5). CONCLUSION: Our work describes the first mutation in the pZRS to be associated with TPT-PS and provides functional evidence that this mutation leads to ectopic expression of this enhancer within the developing limb.
PURPOSE: The zone of polarizing activity regulatory sequence (ZRS) is an enhancer that regulates sonic hedgehog during embryonic limb development. Recently, mutations in a noncoding evolutionary conserved sequence 500 bp upstream of the ZRS, termed the pre-ZRS (pZRS), have been associated with polydactyly in dogs and humans. Here, we report the first case of triphalangeal thumb-polysyndactyly syndrome (TPT-PS) to be associated with mutations in this region and show via mouse enhancer assays how this mutation leads to ectopic expression throughout the developing limb bud. METHODS: We used linkage analysis, whole-exome sequencing, Sanger sequencing, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, single-nucleotide polymorphism array, and a mouse transgenic enhancer assay. RESULTS: Ten members of a TPT-PS family were included in this study. The mutation was linked to chromosome 7q36 (LOD score 3.0). No aberrations in the ZRS could be identified. A point mutation in the pZRS (chr7:156585476G>C; GRCh37/hg19) was detected in all affected family members. Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud (E11.5). CONCLUSION: Our work describes the first mutation in the pZRS to be associated with TPT-PS and provides functional evidence that this mutation leads to ectopic expression of this enhancer within the developing limb.
Authors: Jacob W P Potuijt; Anna Sowinska-Seidler; Ewelina Bukowska-Olech; Picard Nguyen; Aleksander Jankowski; Frank Magielsen; Karolina Matuszewska; Christianne A van Nieuwenhoven; Robert-Jan H Galjaard; Annelies de Klein; Aleksander Jamsheer Journal: Mol Genet Genomics Date: 2022-07-11 Impact factor: 2.980
Authors: Jacob W P Potuijt; Robert-Jan H Galjaard; Peter J van der Spek; Christianne A van Nieuwenhoven; Nadav Ahituv; Kerby C Oberg; Steven E R Hovius Journal: J Hand Surg Eur Vol Date: 2018-10-14
Authors: Qian Cong; Yuchen Liu; Taifeng Zhou; Yaxing Zhou; Ruoshi Xu; Caiqi Cheng; Hye Soo Chung; Meijun Yan; Hang Zhou; Zhiheng Liao; Bo Gao; Geoffrey A Bocobo; Taylor A Covington; Hyeon Ju Song; Peiqiang Su; Paul B Yu; Yingzi Yang Journal: Sci Transl Med Date: 2021-06-23 Impact factor: 19.319