ArticleNature communications2023
Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve split-hand/foot malformation type 3.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 32 citations in OpenAlex.
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- Identification of novel tumor protein 63 variant associated with split-hand/foot malformation and tooth agenesis.Frontiers in medicine · 2026Article
- 3D Chromatin Architecture During Early Development: New Methods and New Findings.Methods in molecular biology (Clifton, N.J.) · 2026Article
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- Chromatin conformation capture in the clinic: 4C-seq/HiC distinguishes pathogenic from neutral duplications at the GPR101 locus.Genome medicine · 2024Article
- TAD border deletion at the Kit locus causes tissue-specific ectopic activation of a neighboring gene.Nature communications · 2024Article
- Variable clinical presentation of split hand/foot malformation syndrome in a family with microduplication of 10q24.32: a case report.Frontiers in genetics · 2023Article
Corrections and comments
- Erratum issued
Authors and funding
17 authors at 9 institutions in 6 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Split-Hand/Foot Malformation type 3 (SHFM3) is a congenital limb malformation associated with tandem duplications at the LBX1/FGF8 locus. Yet, the disease patho-mechanism remains unsolved. Here we investigate the functional consequences of SHFM3-associated rearrangements on chromatin conformation and gene expression in vivo in transgenic mice. We show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. Re-engineering of a SHFM3-associated duplication and a newly reported inversion in mice results in restructuring of the chromatin architecture. This leads to ectopic activation of the Lbx1 and Btrc genes in the apical ectodermal ridge (AER) in an Fgf8-like pattern induced by AER-specific enhancers of Fgf8. We provide evidence that the SHFM3 phenotype is the result of a combinatorial effect on gene misexpression in the developing limb. Our results reveal insights into the molecular mechanism underlying SHFM3 and provide conceptual framework for how genomic rearrangements can cause gene misexpression and disease.
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