ArticleHuman mutation2014
A novel ZRS mutation leads to preaxial polydactyly type 2 in a heterozygous form and Werner mesomelic syndrome in a homozygous form.
Article in Human mutation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 33 citations in OpenAlex.
- From chromatin to proteostasis: multilevel gene regulation in Mendelian diseases.Frontiers in epigenetics and epigenomics · 2026Review
- Genetic analysis of preaxial polydactyly: identification of novel variants and the role of ZRS duplications in a Chinese cohort of 102 cases.Human genetics · 2024Article
- 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
- ZPA Regulatory Sequence Variants in Chinese Patients With Preaxial Polydactyly: Genetic and Clinical Characteristics.Frontiers in pediatrics · 2022Article
- Deletion of CTCF sites in the SHH locus alters enhancer-promoter interactions and leads to acheiropodia.Nature communications · 2021Article
- Variable expression of subclinical phenotypes instead of reduced penetrance in families with mild triphalangeal thumb phenotypes.Journal of medical genetics · 2020Article
- Comprehensive In Vivo Interrogation Reveals Phenotypic Impact of Human Enhancer Variants.Cell · 2020Article
- A multidisciplinary review of triphalangeal thumb.The Journal of hand surgery, European volume · 2019Review
- A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in triphalangeal thumb-polysyndactyly syndrome.Genetics in medicine : official journal of the American College of Medical Genetics · 2018Article
- Zone of Polarizing Activity Regulatory Sequence Mutations/Duplications with Preaxial Polydactyly and Longitudinal Preaxial Ray Deficiency in the Phenotype: A Review of Human Cases, Animal Models, and Insights Regarding the Pathogenesis.BioMed research international · 2018Review
- Identity-by-descent refines mapping of candidate regions for preaxial polydactyly II /III in a large Chinese pedigree.Hereditas · 2018Article
- Intrafamilial variability of the triphalangeal thumb phenotype in a Dutch population: Evidence for phenotypic progression over generations?American journal of medical genetics. Part A · 2017Article
- The Conserved Sonic Hedgehog Limb Enhancer Consists of Discrete Functional Elements that Regulate Precise Spatial Expression.Cell reports · 2017Article
- The two domain hypothesis of limb prepattern and its relevance to congenital limb anomalies.Wiley interdisciplinary reviews. Developmental biology · 2017Review
- Sonic Hedgehog Signaling in Limb Development.Frontiers in cell and developmental biology · 2017Review
- Tibial hemimelia: new classification and reconstructive options.Journal of children's orthopaedics · 2016Review
- Shh and ZRS enhancer colocalisation is specific to the zone of polarising activity.Development (Cambridge, England) · 2016Article
- Tibial hemimelia associated with GLI3 truncation.Journal of human genetics · 2016Article
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Authors and funding
8 authors at 6 institutions in 2 countries.
Funding
Abstract
Point mutations in the zone of polarizing activity regulatory sequence (ZRS) are known to cause human limb malformations. Although most mutations cause preaxial polydactyly (PPD), triphalangeal thumb (TPT) or both, a mutation in position 404 of the ZRS causes more severe Werner mesomelic syndrome (WMS) for which malformations include the distal arm or leg bones in addition to the hands and/or feet. Of more than 15 reported families with ZRS mutations, only one homozygous individual has been reported, with no change in phenotype compared with heterozygotes. Here, we describe a novel point mutation in the ZRS, 402C>T (AC007097.4:g.105548C>T), that is transmitted through two Mexican families with one homozygous individual. The homozygous phenotype for this mutation, WMS, is more severe than the numerous heterozygous individuals genotyped from both families who have TPT and PPD. A mouse transgenic enhancer assay shows that this mutation causes an expansion of the enhancer's expression domain in the developing mouse limb, confirming its pathogenicity. Combined, our results identify a novel ZRS mutation in the Mexican population, 402C>T, and suggest that a dosage effect exists for this ZRS mutation.
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