دورية أكاديمية
Human and mouse studies establish TBX6 in Mendelian CAKUT and as a potential driver of kidney defects associated with the 16p11.2 microdeletion syndrome.
| العنوان: | Human and mouse studies establish TBX6 in Mendelian CAKUT and as a potential driver of kidney defects associated with the 16p11.2 microdeletion syndrome. |
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| المؤلفون: | Yang N; Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China; State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China., Wu N; Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, China; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Dong S; Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China., Zhang L; Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, China., Zhao Y; Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China., Chen W; Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China., Du R; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Song C; Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China., Ren X; Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China., Liu J; Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China., Pehlivan D; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Texas Children's Hospital, Houston, Texas, USA., Liu Z; Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China., Rao J; Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China; Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China., Wang C; Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China; Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China., Zhao S; Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China., Breman AM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Baylor Genetics, Houston, Texas, USA., Xue H; Department of Radiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China., Sun H; Department of Radiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China., Shen J; Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, China., Zhang S; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China., Posey JE; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Xu H; Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China; Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China., Jin L; Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, China., Zhang J; Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, China., Liu P; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Baylor Genetics, Houston, Texas, USA., Sanna-Cherchi S; Division of Nephrology, Department of Medicine, Columbia University, New York, USA., Qiu G; Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, China., Wu Z; Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China., Lupski JR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Texas Children's Hospital, Houston, Texas, USA; Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA., Zhang F; Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China; State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. Electronic address: zhangfeng@fudan.edu.cn. |
| المصدر: | Kidney international [Kidney Int] 2020 Oct; Vol. 98 (4), pp. 1020-1030. Date of Electronic Publication: 2020 May 22. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 0323470 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1523-1755 (Electronic) Linking ISSN: 00852538 NLM ISO Abbreviation: Kidney Int Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2016- : New York : Elsevier Original Publication: New York, Springer-Verlag. |
| مواضيع طبية MeSH: | Scoliosis*, Animals ; Humans ; Kidney ; Mice ; Retrospective Studies ; T-Box Domain Proteins/genetics ; Urogenital Abnormalities ; Vesico-Ureteral Reflux |
| مستخلص: | Congenital anomalies of the kidney and urinary tract (CAKUTs) are the most common cause of chronic kidney disease in children. Human 16p11.2 deletions have been associated with CAKUT, but the responsible molecular mechanism remains to be illuminated. To explore this, we investigated 102 carriers of 16p11.2 deletion from multi-center cohorts, among which we retrospectively ascertained kidney morphologic and functional data from 37 individuals (12 Chinese and 25 Caucasian/Hispanic). Significantly higher CAKUT rates were observed in 16p11.2 deletion carriers (about 25% in Chinese and 16% in Caucasian/Hispanic) than those found in the non-clinically ascertained general populations (about 1/1000 found at autopsy). Furthermore, we identified seven additional individuals with heterozygous loss-of-function variants in TBX6, a gene that maps to the 16p11.2 region. Four of these seven cases showed obvious CAKUT. To further investigate the role of TBX6 in kidney development, we engineered mice with mutated Tbx6 alleles. The Tbx6 heterozygous null (i.e., loss-of-function) mutant (Tbx6 +/‒ ) resulted in 13% solitary kidneys. Remarkably, this incidence increased to 29% in a compound heterozygous model (Tbx6 mh/‒ ) that reduced Tbx6 gene dosage to below haploinsufficiency, by combining the null allele with a novel mild hypomorphic allele (mh). Renal hypoplasia was also frequently observed in these Tbx6-mutated mouse models. Thus, our findings in patients and mice establish TBX6 as a novel gene involved in CAKUT and its gene dosage insufficiency as a potential driver for kidney defects observed in the 16p11.2 microdeletion syndrome. (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.) |
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| معلومات مُعتمدة: | P20 DK116191 United States DK NIDDK NIH HHS; UM1 HG006542 United States HG NHGRI NIH HHS; R35 NS105078 United States NS NINDS NIH HHS; K08 HG008986 United States HG NHGRI NIH HHS; R01 DK103184 United States DK NIDDK NIH HHS; R01 DK115574 United States DK NIDDK NIH HHS |
| فهرسة مساهمة: | Keywords: 16p11.2 deletion; CNV; allelic series; compound inheritance; gene dosage; gene expression; kidney development |
| المشرفين على المادة: | 0 (T-Box Domain Proteins) 0 (TBX6 protein, human) 0 (Tbx6 protein, mouse) |
| SCR Disease Name: | Cakut |
| تواريخ الأحداث: | Date Created: 20200526 Date Completed: 20210621 Latest Revision: 20211002 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC7673260 |
| DOI: | 10.1016/j.kint.2020.04.045 |
| PMID: | 32450157 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1523-1755 |
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| DOI: | 10.1016/j.kint.2020.04.045 |