Details

Autor(en) / Beteiligte

• Ren, Xiaojun
• Yang, Nan
• Wu, Nan
• Xu, Ximing
• Chen, Weisheng
• Zhang, Ling
• Li, Yingping
• Du, Ren-Qian
• Dong, Shuangshuang
• Zhao, Sen
• Chen, Shuxia
• Jiang, Li-Ping
• Wang, Lianlei
• Zhang, Jianguo
• Wu, Zhihong
• Jin, Li
• Qiu, Guixing
• Lupski, James R
• Shi, Jiangang
• Zhang, Feng
• Liu, Pengfei

Titel

Increased TBX6 gene dosages induce congenital cervical vertebral malformations in humans and mice

Ist Teil von

• Journal of medical genetics, 2020-06, Vol.57 (6), p.371

Ort / Verlag

England

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• Congenital vertebral malformations (CVMs) manifest with abnormal vertebral morphology. Genetic factors have been implicated in CVM pathogenesis, but the underlying pathogenic mechanisms remain unclear in most subjects. We previously reported that the human 16p11.2 BP4-BP5 deletion and its associated dosage reduction caused CVMs. We aim to investigate the reciprocal 16p11.2 BP4-BP5 duplication and its potential genetic contributions to CVMs. Patients who were found to carry the 16p11.2 BP4-BP5 duplication by chromosomal microarray analysis were retrospectively analysed for their vertebral phenotypes. The spinal assessments in seven duplication carriers showed that four (57%) presented characteristics of CVMs, supporting the contention that increased dosage could induce CVMs. For further in vivo functional investigation in a model organism, we conducted genome editing of the upstream regulatory region of mouse using CRISPR-Cas9 and obtained three mouse mutant alleles ( to ) with elevated expression levels of . Luciferase reporter assays showed that the allele presented with the 160% expression level of that observed in the reference (+) allele. Therefore, the homozygous mice could functionally mimic the dosage of heterozygous carriers of 16p11.2 BP4-BP5 duplication (approximately 150%, ie, 3/2 gene dosage of the normal level). Remarkably, 60% of the mice manifested with CVMs. Consistent with our observations in humans, the CVMs induced by increased dosage in mice mainly affected the cervical vertebrae. Our findings in humans and mice consistently support that an increased dosage contributes to the risk of developing cervical CVMs.