Format

Send to

Choose Destination
Hum Mol Genet. 2019 Feb 15;28(4):539-547. doi: 10.1093/hmg/ddy358.

TBX6 compound inheritance leads to congenital vertebral malformations in humans and mice.

Yang N1,2,3, Wu N4,5,6,7, Zhang L1, Zhao Y4,5, Liu J4,5, Liang X8, Ren X1, Li W1, Chen W4,5, Dong S1, Zhao S4,5, Lin J4,5, Xiang H1, Xue H9, Chen L1, Sun H9, Zhang J4,5,6, Shi J10, Zhang S5,11, Lu D1, Wu X12, Jin L1, Ding J8, Qiu G4,5,6, Wu Z4,5,13, Lupski JR7,14,15, Zhang F1,2,3.

Author information

1
Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Fudan University, Shanghai, China.
2
Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
3
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
4
Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
5
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China.
6
Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, China.
7
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA.
8
State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai, China.
9
Department of Radiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
10
Second Department of Spine Surgery, Changzheng Hospital, The Second Military Medical University, Shanghai, China.
11
Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
12
Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Institute of Developmental Biology and Molecular Medicine, Fudan University, Shanghai, China.
13
Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
14
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
15
Texas Children's Hospital, Houston, TX, USA.

Abstract

Congenital vertebral malformations (CVMs) are associated with human TBX6 compound inheritance that combines a rare null allele and a common hypomorphic allele at the TBX6 locus. Our previous in vitro evidence suggested that this compound inheritance resulted in a TBX6 gene dosage of less than haploinsufficiency (i.e. <50%) as a potential mechanism of TBX6-associated CVMs. To further investigate this pathogenetic model, we ascertained and collected 108 Chinese CVM cases and found that 10 (9.3%) of them carried TBX6 null mutations in combination with common hypomorphic variants at the second TBX6 allele. For in vivo functional verification and genetic analysis of TBX6 compound inheritance, we generated both null and hypomorphic mutations in mouse Tbx6 using the CRISPR-Cas9 method. These Tbx6 mutants are not identical to the patient variants at the DNA sequence level, but instead functionally mimic disease-associated TBX6 variants. Intriguingly, as anticipated by the compound inheritance model, a high penetrance of CVM phenotype was only observed in the mice with combined null and hypomorphic alleles of Tbx6. These findings are consistent with our experimental observations in humans and supported the dosage effect of TBX6 in CVM etiology. In conclusion, our findings in the newly collected human CVM subjects and Tbx6 mouse models consistently support the contention that TBX6 compound inheritance causes CVMs, potentially via a gene dosage-dependent mechanism. Furthermore, mouse Tbx6 mutants mimicking human CVM-associated variants will be useful models for further mechanistic investigations of CVM pathogenesis in the cases associated with TBX6.

PMID:
30307510
DOI:
10.1093/hmg/ddy358

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center