A novel ZRS variant causes preaxial polydactyly type I by increased sonic hedgehog expression in the developing limb bud
A novel ZRS variant causes preaxial polydactyly type I by increased sonic hedgehog expression in the developing limb bud
复制标题
一种新的 ZRS 变异通过增加发育中的肢芽中的音刺猬表达而导致 I 型轴前多指畸形
DOI：
10.1038/s41436-019-0626-7
复制
发表时间：
2020-01-01
影响因子：
8.8
通讯作者：
Su, Peiqiang
中科院分区：
文献类型：
--
作者：
Xu, Caixia;Yang, Xiaoming;Su, Peiqiang
Purpose Preaxial polydactyly (PPD) is a common congenital hand malformation classified into four subtypes (PPD I-IV). Variants in the zone of polarizing activity regulatory sequence (ZRS) within intron 5 of the LMBR1 gene are linked to most PPD types. However, the genes responsible for PPD I and the underlying mechanisms are unknown. Methods A rare large four-generation family with isolated PPD I was subjected to genome-wide genotyping and sequence analysis. In vitro and in vivo functional studies were performed in Caco-2 cells, 293T cells, and a knockin transgenic mouse model. Results A novel g.101779T>A (reference sequence: NG_009240.2; position 446 of the ZRS) variant segregates with all PPD I-affected individuals. The knockin mouse with this ZRS variant exhibited PPD I phenotype accompanying ectopic and excess expression of Shh. We confirmed that HnRNP K can bind the ZRS and SHH promoters. The ZRS mutant enhanced the binding affinity for HnRNP K and upregulated SHH expression. Conclusion Our results identify the first PPD I disease-causing variant. The variant leading to PPD I may be associated with enhancing SHH expression mediated by HnRNP K. This study adds to the ZRS-associated syndromes classification system for PPD and clarifies the underlying molecular mechanisms.
