Ontology highlight
ABSTRACT: 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.
SUBMITTER: Xu C
PROVIDER: S-EPMC6944640 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
Xu Caixia C Yang Xiaoming X Zhou Hang H Li Yongyong Y Xing Chao C Zhou Taifeng T Zhong Dongmei D Lian Chengjie C Yan Mei M Chen Tao T Liao Zhiheng Z Gao Bo B Su Deying D Wang Tingting T Sharma Swarkar S Mohan Chandra C Ahituv Nadav N Malik Sajid S Li Quan-Zhen QZ Su Peiqiang P
Genetics in medicine : official journal of the American College of Medical Genetics 20190809 1
<h4>Purpose</h4>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.<h4>Methods</h4>A rare large four-generation family with isolated PPD I was subjected to genome-wide genotyping and sequence analysis. In vitro and in vivo f ...[more]