@article {954,
	title = {Human and mouse studies establish TBX6 in Mendelian CAKUT and as a potential driver of kidney defects associated with the 16p11.2 microdeletion syndrome.},
	journal = {Kidney Int},
	volume = {98},
	year = {2020},
	month = {2020 10},
	pages = {1020-1030},
	abstract = {<p>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) 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.</p>},
	issn = {1523-1755},
	doi = {10.1016/j.kint.2020.04.045},
	author = {Yang, Nan and Wu, Nan and Dong, Shuangshuang and Zhang, Ling and Zhao, Yanxue and Chen, Weisheng and Du, Renqian and Song, Chengcheng and Ren, Xiaojun and Liu, Jiaqi and Pehlivan, Davut and Liu, Zhenlei and Rao, Jia and Wang, Chunyan and Zhao, Sen and Breman, Amy M and Xue, Huadan and Sun, Hao and Shen, Jianxiong and Zhang, Shuyang and Posey, Jennifer E and Xu, Hong and Jin, Li and Zhang, Jianguo and Liu, Pengfei and Sanna-Cherchi, Simone and Qiu, Guixing and Wu, Zhihong and Lupski, James R and Zhang, Feng}
}
@article {570,
	title = {TBX6 compound inheritance leads to congenital vertebral malformations in humans and mice.},
	journal = {Hum Mol Genet},
	volume = {28},
	year = {2019},
	month = {2019 02 15},
	pages = {539-547},
	abstract = {<p>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.</p>},
	keywords = {Adolescent, Alleles, Animals, Child, Child, Preschool, Congenital Abnormalities, CRISPR-Cas Systems, Disease Models, Animal, Female, Haploinsufficiency, Humans, Infant, Male, Mice, Mutation, Phenotype, Scoliosis, Spine, T-Box Domain Proteins},
	issn = {1460-2083},
	doi = {10.1093/hmg/ddy358},
	author = {Yang, Nan and Wu, Nan and Zhang, Ling and Zhao, Yanxue and Liu, Jiaqi and Liang, Xiangyu and Ren, Xiaojun and Li, Weiyu and Chen, Weisheng and Dong, Shuangshuang and Zhao, Sen and Lin, Jiachen and Xiang, Hang and Xue, Huadan and Chen, Lu and Sun, Hao and Zhang, Jianguo and Shi, Jiangang and Zhang, Shuyang and Lu, Daru and Wu, Xiaohui and Jin, Li and Ding, Jiandong and Qiu, Guixing and Wu, Zhihong and Lupski, James R and Zhang, Feng}
}
