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 journalArticle

2 Citations (Scopus)

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)
JournalGenetics in Medicine
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Polydactyly
Limb Buds
Hedgehogs
Caco-2 Cells
HEK293 Cells
Introns
Transgenic Mice
Genes
Sequence Analysis
Hand
Polydactyly preaxial type 1
Genome
Phenotype

Keywords

  • gene regulation
  • preaxial polydactyly
  • sonic hedgehog
  • ZRS

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

A novel ZRS variant causes preaxial polydactyly type I by increased sonic hedgehog expression in the developing limb bud. / Xu, Caixia; Yang, Xiaoming; Zhou, Hang; Li, Yongyong; Xing, Chao; Zhou, Taifeng; Zhong, Dongmei; Lian, Chengjie; Yan, Mei; Chen, Tao; Liao, Zhiheng; Gao, Bo; Su, Deying; Wang, Tingting; Sharma, Swarkar; Mohan, Chandra; Ahituv, Nadav; Malik, Sajid; Li, Quan Zhen; Su, Peiqiang.

In: Genetics in Medicine, 01.01.2019.

Research output: Contribution to journalArticle

Xu, C, Yang, X, Zhou, H, Li, Y, Xing, C, Zhou, T, Zhong, D, Lian, C, Yan, M, Chen, T, Liao, Z, Gao, B, Su, D, Wang, T, Sharma, S, Mohan, C, Ahituv, N, Malik, S, Li, QZ & Su, P 2019, 'A novel ZRS variant causes preaxial polydactyly type I by increased sonic hedgehog expression in the developing limb bud', Genetics in Medicine. https://doi.org/10.1038/s41436-019-0626-7
Xu, Caixia ; Yang, Xiaoming ; Zhou, Hang ; Li, Yongyong ; Xing, Chao ; Zhou, Taifeng ; Zhong, Dongmei ; Lian, Chengjie ; Yan, Mei ; Chen, Tao ; Liao, Zhiheng ; Gao, Bo ; Su, Deying ; Wang, Tingting ; Sharma, Swarkar ; Mohan, Chandra ; Ahituv, Nadav ; Malik, Sajid ; Li, Quan Zhen ; Su, Peiqiang. / A novel ZRS variant causes preaxial polydactyly type I by increased sonic hedgehog expression in the developing limb bud. In: Genetics in Medicine. 2019.
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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.",
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AU - Xu, Caixia

AU - Yang, Xiaoming

AU - Zhou, Hang

AU - Li, Yongyong

AU - Xing, Chao

AU - Zhou, Taifeng

AU - Zhong, Dongmei

AU - Lian, Chengjie

AU - Yan, Mei

AU - Chen, Tao

AU - Liao, Zhiheng

AU - Gao, Bo

AU - Su, Deying

AU - Wang, Tingting

AU - Sharma, Swarkar

AU - Mohan, Chandra

AU - Ahituv, Nadav

AU - Malik, Sajid

AU - Li, Quan Zhen

AU - Su, Peiqiang

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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