Deleterious Rare Mutations of GLI1 Dysregulate Sonic Hedgehog Signaling in Human Congenital Heart Disease
The Glioma-associated oncogene (Gli) family members of zinc finger DNA-binding proteins are core effectors of Sonic hedgehog (SHH) signaling pathway. Studies in model organisms have identified that the Gli genes play critical roles during organ development, including the heart, brain, kidneys, etc....
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-04-01
|
| Series: | Frontiers in Cardiovascular Medicine |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2022.798033/full |
| _version_ | 1818355545229230080 |
|---|---|
| author | Rui Peng Rui Peng Binbin Li Binbin Li Shuxia Chen Shuxia Chen Zhiwen Shi Zhiwen Shi Liwei Yu Liwei Yu Yunqian Gao Yunqian Gao Xueyan Yang Xueyan Yang Lei Lu Lei Lu Hongyan Wang Hongyan Wang |
| author_facet | Rui Peng Rui Peng Binbin Li Binbin Li Shuxia Chen Shuxia Chen Zhiwen Shi Zhiwen Shi Liwei Yu Liwei Yu Yunqian Gao Yunqian Gao Xueyan Yang Xueyan Yang Lei Lu Lei Lu Hongyan Wang Hongyan Wang |
| author_sort | Rui Peng |
| collection | DOAJ |
| description | The Glioma-associated oncogene (Gli) family members of zinc finger DNA-binding proteins are core effectors of Sonic hedgehog (SHH) signaling pathway. Studies in model organisms have identified that the Gli genes play critical roles during organ development, including the heart, brain, kidneys, etc. Deleterious mutations in GLI genes have previously been revealed in several human developmental disorders, but few in congenital heart disease (CHD). In this study, the mutations in GLI1-3 genes were captured by next generation sequencing in human cohorts composed of 412 individuals with CHD and 213 ethnically matched normal controls. A total of 20 patient-specific nonsynonymous rare mutations in coding regions of human GLI1-3 genes were identified. Functional analyses showed that GLI1 c.820G> T (p.G274C) is a gain-of-function mutation, while GLI1 c.878G>A (p.R293H) and c.1442T>A (p.L481X) are loss-of-function mutations. Our findings suggested that deleterious rare mutations in GLI1 gene broke the balance of the SHH signaling pathway regulation and may constitute a great contribution to human CHD, which shed new light on understanding genetic mechanism of embryo cardiogenesis regulated by SHH signaling. |
| first_indexed | 2024-12-13T19:43:01Z |
| format | Article |
| id | doaj.art-5d3c063b2e94492a89b3859bbfbac968 |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-12-13T19:43:01Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-5d3c063b2e94492a89b3859bbfbac9682022-12-21T23:33:38ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2022-04-01910.3389/fcvm.2022.798033798033Deleterious Rare Mutations of GLI1 Dysregulate Sonic Hedgehog Signaling in Human Congenital Heart DiseaseRui Peng0Rui Peng1Binbin Li2Binbin Li3Shuxia Chen4Shuxia Chen5Zhiwen Shi6Zhiwen Shi7Liwei Yu8Liwei Yu9Yunqian Gao10Yunqian Gao11Xueyan Yang12Xueyan Yang13Lei Lu14Lei Lu15Hongyan Wang16Hongyan Wang17NHC Key Laboratory of Reproduction Regulation, State Key Laboratory of Genetic Engineering, Obstetrics and Gynecology Hospital, Shanghai Institute of Planned Parenthood Research, Institute of Reproduction and Development, Children's Hospital, Fudan University, Shanghai, ChinaShanghai Key Laboratory of Metabolic Remodeling and Health, School of Life Sciences, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, ChinaDepartment of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO, United StatesCenter for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, United StatesNHC Key Laboratory of Reproduction Regulation, State Key Laboratory of Genetic Engineering, Obstetrics and Gynecology Hospital, Shanghai Institute of Planned Parenthood Research, Institute of Reproduction and Development, Children's Hospital, Fudan University, Shanghai, ChinaShanghai Key Laboratory of Metabolic Remodeling and Health, School of Life Sciences, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, ChinaNHC Key Laboratory of Reproduction Regulation, State Key Laboratory of Genetic Engineering, Obstetrics and Gynecology Hospital, Shanghai Institute of Planned Parenthood Research, Institute of Reproduction and Development, Children's Hospital, Fudan University, Shanghai, ChinaShanghai Key Laboratory of Metabolic Remodeling and Health, School of Life Sciences, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, ChinaNHC Key Laboratory of Reproduction Regulation, State Key Laboratory of Genetic Engineering, Obstetrics and Gynecology Hospital, Shanghai Institute of Planned Parenthood Research, Institute of Reproduction and Development, Children's Hospital, Fudan University, Shanghai, ChinaSUNY Downstate Medical Center, Children's Hospital at Downstate, Brooklyn, NY, United StatesNHC Key Laboratory of Reproduction Regulation, State Key Laboratory of Genetic Engineering, Obstetrics and Gynecology Hospital, Shanghai Institute of Planned Parenthood Research, Institute of Reproduction and Development, Children's Hospital, Fudan University, Shanghai, ChinaDepartment of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaNHC Key Laboratory of Reproduction Regulation, State Key Laboratory of Genetic Engineering, Obstetrics and Gynecology Hospital, Shanghai Institute of Planned Parenthood Research, Institute of Reproduction and Development, Children's Hospital, Fudan University, Shanghai, ChinaShanghai Key Laboratory of Metabolic Remodeling and Health, School of Life Sciences, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, ChinaNHC Key Laboratory of Reproduction Regulation, State Key Laboratory of Genetic Engineering, Obstetrics and Gynecology Hospital, Shanghai Institute of Planned Parenthood Research, Institute of Reproduction and Development, Children's Hospital, Fudan University, Shanghai, ChinaShanghai Key Laboratory of Metabolic Remodeling and Health, School of Life Sciences, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, ChinaNHC Key Laboratory of Reproduction Regulation, State Key Laboratory of Genetic Engineering, Obstetrics and Gynecology Hospital, Shanghai Institute of Planned Parenthood Research, Institute of Reproduction and Development, Children's Hospital, Fudan University, Shanghai, ChinaShanghai Key Laboratory of Metabolic Remodeling and Health, School of Life Sciences, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, ChinaThe Glioma-associated oncogene (Gli) family members of zinc finger DNA-binding proteins are core effectors of Sonic hedgehog (SHH) signaling pathway. Studies in model organisms have identified that the Gli genes play critical roles during organ development, including the heart, brain, kidneys, etc. Deleterious mutations in GLI genes have previously been revealed in several human developmental disorders, but few in congenital heart disease (CHD). In this study, the mutations in GLI1-3 genes were captured by next generation sequencing in human cohorts composed of 412 individuals with CHD and 213 ethnically matched normal controls. A total of 20 patient-specific nonsynonymous rare mutations in coding regions of human GLI1-3 genes were identified. Functional analyses showed that GLI1 c.820G> T (p.G274C) is a gain-of-function mutation, while GLI1 c.878G>A (p.R293H) and c.1442T>A (p.L481X) are loss-of-function mutations. Our findings suggested that deleterious rare mutations in GLI1 gene broke the balance of the SHH signaling pathway regulation and may constitute a great contribution to human CHD, which shed new light on understanding genetic mechanism of embryo cardiogenesis regulated by SHH signaling.https://www.frontiersin.org/articles/10.3389/fcvm.2022.798033/fullcongenital heart disease (CHD)GLI1genetic variantrare mutationSonic hedgehog (SHH) signaling pathway |
| spellingShingle | Rui Peng Rui Peng Binbin Li Binbin Li Shuxia Chen Shuxia Chen Zhiwen Shi Zhiwen Shi Liwei Yu Liwei Yu Yunqian Gao Yunqian Gao Xueyan Yang Xueyan Yang Lei Lu Lei Lu Hongyan Wang Hongyan Wang Deleterious Rare Mutations of GLI1 Dysregulate Sonic Hedgehog Signaling in Human Congenital Heart Disease Frontiers in Cardiovascular Medicine congenital heart disease (CHD) GLI1 genetic variant rare mutation Sonic hedgehog (SHH) signaling pathway |
| title | Deleterious Rare Mutations of GLI1 Dysregulate Sonic Hedgehog Signaling in Human Congenital Heart Disease |
| title_full | Deleterious Rare Mutations of GLI1 Dysregulate Sonic Hedgehog Signaling in Human Congenital Heart Disease |
| title_fullStr | Deleterious Rare Mutations of GLI1 Dysregulate Sonic Hedgehog Signaling in Human Congenital Heart Disease |
| title_full_unstemmed | Deleterious Rare Mutations of GLI1 Dysregulate Sonic Hedgehog Signaling in Human Congenital Heart Disease |
| title_short | Deleterious Rare Mutations of GLI1 Dysregulate Sonic Hedgehog Signaling in Human Congenital Heart Disease |
| title_sort | deleterious rare mutations of gli1 dysregulate sonic hedgehog signaling in human congenital heart disease |
| topic | congenital heart disease (CHD) GLI1 genetic variant rare mutation Sonic hedgehog (SHH) signaling pathway |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2022.798033/full |
| work_keys_str_mv | AT ruipeng deleteriousraremutationsofgli1dysregulatesonichedgehogsignalinginhumancongenitalheartdisease AT ruipeng deleteriousraremutationsofgli1dysregulatesonichedgehogsignalinginhumancongenitalheartdisease AT binbinli deleteriousraremutationsofgli1dysregulatesonichedgehogsignalinginhumancongenitalheartdisease AT binbinli deleteriousraremutationsofgli1dysregulatesonichedgehogsignalinginhumancongenitalheartdisease AT shuxiachen deleteriousraremutationsofgli1dysregulatesonichedgehogsignalinginhumancongenitalheartdisease AT shuxiachen deleteriousraremutationsofgli1dysregulatesonichedgehogsignalinginhumancongenitalheartdisease AT zhiwenshi deleteriousraremutationsofgli1dysregulatesonichedgehogsignalinginhumancongenitalheartdisease AT zhiwenshi deleteriousraremutationsofgli1dysregulatesonichedgehogsignalinginhumancongenitalheartdisease AT liweiyu deleteriousraremutationsofgli1dysregulatesonichedgehogsignalinginhumancongenitalheartdisease AT liweiyu deleteriousraremutationsofgli1dysregulatesonichedgehogsignalinginhumancongenitalheartdisease AT yunqiangao deleteriousraremutationsofgli1dysregulatesonichedgehogsignalinginhumancongenitalheartdisease AT yunqiangao deleteriousraremutationsofgli1dysregulatesonichedgehogsignalinginhumancongenitalheartdisease AT xueyanyang deleteriousraremutationsofgli1dysregulatesonichedgehogsignalinginhumancongenitalheartdisease AT xueyanyang deleteriousraremutationsofgli1dysregulatesonichedgehogsignalinginhumancongenitalheartdisease AT leilu deleteriousraremutationsofgli1dysregulatesonichedgehogsignalinginhumancongenitalheartdisease AT leilu deleteriousraremutationsofgli1dysregulatesonichedgehogsignalinginhumancongenitalheartdisease AT hongyanwang deleteriousraremutationsofgli1dysregulatesonichedgehogsignalinginhumancongenitalheartdisease AT hongyanwang deleteriousraremutationsofgli1dysregulatesonichedgehogsignalinginhumancongenitalheartdisease |