ArticleCell research2011
Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels.
Article in Cell research, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 53 citations in OpenAlex.
- Ubiquitin Ligases in pro-atrophic and antiatrophic signaling cascades in muscles.Molecular biology reports · 2026Review
- Spatiotemporal Regulation and Lineage Specification in Embryonic Endochondral Ossification.International journal of molecular sciences · 2026Review
- A Novel HeterozygousPhenomics (Cham, Switzerland) · 2025Article
- Suppression of apoptosis impairs phalangeal joint formation in the pathogenesis of brachydactyly type A1.Nature communications · 2024Article
- Article
- SAG therapy restores bone growth and reduces enchondroma incidence in a model of skeletal chondrodysplasias caused by Ihh deficiency.Molecular therapy. Methods & clinical development · 2021Article
- Deletion of 2 amino acids in IHH in a Japanese family with brachydactyly type A1.BMC medical genomics · 2021Article
- Highly ConservedBiomolecules · 2021Article
- To Breathe or Not to Breathe: The Role of Oxygen in Bone Marrow-Derived Mesenchymal Stromal Cell Senescence.Stem cells international · 2021Review
- RNA-seq reveals downregulated osteochondral genes potentially related to tibia bacterial chondronecrosis with osteomyelitis in broilers.BMC genetics · 2020Article
- Article
- A novel variant of IHH in a Chinese family with brachydactyly type 1.BMC medical genetics · 2020Article
- Recent Insights into Long Bone Development: Central Role of Hedgehog Signaling Pathway in Regulating Growth Plate.International journal of molecular sciences · 2019Review
- p.E95K mutation in Indian hedgehog causing brachydactyly type A1 impairs IHH/Gli1 downstream transcriptional regulation.BMC genetics · 2019Article
- The Effects of Indian Hedgehog Deletion on Mesenchyme Cells: Inducing Intermediate Cartilage Scaffold Ossification to Cause Growth Plate and Phalange Joint Absence, Short Limb, and Dwarfish Phenotypes.Stem cells and development · 2018Article
- Whole-exome sequencing identifies a novelSAGE open medical case reports · 2018Article
- Genetic advances in craniosynostosis.American journal of medical genetics. Part A · 2017Review
- Regulatory Mechanisms of the Ihh/PTHrP Signaling Pathway in Fibrochondrocytes in Entheses of Pig Achilles Tendon.Stem cells international · 2016Article
- Identification of p.Glu131Lys Mutation in the IHH Gene in a Korean Patient With Brachydactyly Type A1.Annals of laboratory medicine · 2015Article
- Identification of duplication downstream of BMP2 in a Chinese family with brachydactyly type A2 (BDA2).PloS one · 2014Article
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Authors and funding
19 authors at 9 institutions in 2 countries.
Funding
Abstract
Brachydactyly type A1 (BDA1), the first recorded Mendelian autosomal dominant disorder in humans, is characterized by a shortening or absence of the middle phalanges. Heterozygous missense mutations in the Indian Hedgehog (IHH) gene have been identified as a cause of BDA1; however, the biochemical consequences of these mutations are unclear. In this paper, we analyzed three BDA1 mutations (E95K, D100E, and E131K) in the N-terminal fragment of Indian Hedgehog (IhhN). Structural analysis showed that the E95K mutation changes a negatively charged area to a positively charged area in a calcium-binding groove, and that the D100E mutation changes the local tertiary structure. Furthermore, we showed that the E95K and D100E mutations led to a temperature-sensitive and calcium-dependent instability of IhhN, which might contribute to an enhanced intracellular degradation of the mutant proteins via the lysosome. Notably, all three mutations affected Hh binding to the receptor Patched1 (PTC1), reducing its capacity to induce cellular differentiation. We propose that these are common features of the mutations that cause BDA1, affecting the Hh tertiary structure, intracellular fate, binding to the receptor/partners, and binding to extracellular components. The combination of these features alters signaling capacity and range, but the impact is likely to be variable and mutation-dependent. The potential variation in the signaling range is characterized by an enhanced interaction with heparan sulfate for IHH with the E95K mutation, but not the E131K mutation. Taken together, our results suggest that these IHH mutations affect Hh signaling at multiple levels, causing abnormal bone development and abnormal digit formation.
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