ArticleGenetics in medicine : official journal of the American College of Medical Genetics2020
A novel ZRS variant causes preaxial polydactyly type I by increased sonic hedgehog expression in the developing limb bud.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed, 26 citations in OpenAlex.
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- Engineering human neuronal diversity: Morphogens and stem cell technologies for neurodevelopmental biology.Stem cell reports · 2025Review
- Clinical efficacy of different surgical timing options in the treatment of congenital pediatric polydactyly.Pakistan journal of medical sciences · 2025Article
- Rapid and quantitative functional interrogation of human enhancer variant activity in live mice.Nature communications · 2025Article
- Diversity ofFrontiers in cell and developmental biology · 2025Article
- The First Patient with Tibial Hemimelia-Polysyndactyly-Triphalangeal Thumb Syndrome Caused by De Novo c.423+4916 T>C ZRS Variant: A Case Report.International journal of molecular sciences · 2024Article
- Hnrnpk protects against osteoarthritis through targeting WWC1 mRNA and inhibiting Hippo signaling pathway.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Rapid and Quantitative Functional Interrogation of Human Enhancer Variant Activity in Live Mice.bioRxiv : the preprint server for biology · 2023Article
- Hnrnpk is essential for embryonic limb bud development as a transcription activator and a collaborator of insulator protein Ctcf.Cell death and differentiation · 2023Article
- WGS Revealed NovelInternational journal of molecular sciences · 2023Article
- Polydactyly: Clinical and molecular manifestations.World journal of orthopedics · 2023Review
- TATTOO-seq delineates spatial and cell type-specific regulatory programs in the developing limb.Science advances · 2022Article
- Two nonsense GLI3 variants are associated with polydactyly and syndactyly in two families by affecting the sonic hedgehog signaling pathway.Molecular genetics & genomic medicine · 2022Article
- ZPA Regulatory Sequence Variants in Chinese Patients With Preaxial Polydactyly: Genetic and Clinical Characteristics.Frontiers in pediatrics · 2022Article
- GLIS Family Zinc Finger 1 was First Linked With Preaxial Polydactyly I in Humans by Stepwise Genetic Analysis.Frontiers in cell and developmental biology · 2021Article
- Response to Potuijt et al.Genetics in medicine : official journal of the American College of Medical Genetics · 2020Article
- It all begins with the phenotype.Genetics in medicine : official journal of the American College of Medical Genetics · 2020Article
- Comprehensive In Vivo Interrogation Reveals Phenotypic Impact of Human Enhancer Variants.Cell · 2020Article
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Authors and funding
20 authors at 7 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposePreaxial 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.
methodsA 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.
resultsA 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.
conclusionOur 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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