A novel ZRS variant causes preaxial polydactyly type I by increased sonic hedgehog expression in the developing limb bud

Caixia Xu, Xiaoming Yang, Hang Zhou, Yongyong Li, Chao Xing, Taifeng Zhou, Dongmei Zhong, Chengjie Lian, Mei Yan, Tao Chen, Zhiheng Liao, Bo Gao, Deying Su, Tingting Wang, Swarkar Sharma, Chandra Mohan, Nadav Ahituv, Sajid Malik, Quan Zhen Li, Peiqiang Su

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)189-198
Number of pages10
JournalGenetics in Medicine
Volume22
Issue number1
DOIs
StatePublished - Jan 1 2020

Keywords

  • ZRS
  • gene regulation
  • preaxial polydactyly
  • sonic hedgehog

ASJC Scopus subject areas

  • Genetics(clinical)

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