The DOI matches its Crossref record; 34 of the 35 references it cites were found in a registry or an index.
A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly
Open accessAbstract
Unequivocal identification of the full composition of a gene is made difficult by the cryptic nature of regulatory elements. Regulatory elements are notoriously difficult to locate and may reside at considerable distances from the transcription units on which they operate and, moreover, may be incorporated into the structure of neighbouring genes. The importance of regulatory mutations as the basis of human abnormalities remains obscure. Here, we show that the chromosome 7q36 associated preaxial polydactyly, a frequently observed congenital limb malformation, results from point mutations in a Shh regulatory element. Shh, normally expressed in the ZPA posteriorly in the limb bud, is expressed in an additional ectopic site at the anterior margin in mouse models of PPD. Our investigations into the basis of the ectopic Shh expression identified the enhancer element that drives normal Shh expression in the ZPA. The regulator, designated ZRS, lies within intron 5 of the Lmbr1 gene 1 Mb from the target gene Shh. The ZRS drives the early spatio-temporal expression pattern in the limb of tetrapods. Despite the morphological differences between limbs and fins, an equivalent regulatory element is found in fish. The ZRS contains point mutations that segregate with polydactyly in four unrelated families with PPD and in the Hx mouse mutant. Thus point mutations residing in long-range regulatory elements are capable of causing congenital abnormalities, and possess the capacity to modify gene activity such that a novel gamut of abnormalities is detected.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“It soon became clear that enhancers also played vital roles in humans, with non-coding enhancer deletions starting to be linked to severe disease phenotypes such as beta thalassaemia and polydactyly [25–28].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [27]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The classic example of this is the Shh ZRS enhancer, which is located within the intron of the Lmbr1 gene approximately 1 megabase distant from Shh [27].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [27]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“For example, in the mouse genome, the Shh gene and its ZRS (zone of polarizing activity regulatory sequence) enhancer are located about 1 Mb apart [127].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [127]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“At least a few enhancers reside at great distances from their target gene (e.g. the ZRS enhancer located 1 Mb from the Shh gene118, and a MYC enhancer located 1.7 Mb downstream119), although most are much more proximal to their target promoters72.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [118]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Thompson, J. (1997) · Nucleic Acids Research · doi:10.1093/nar/25.24.4876 · Cited by 38,685
A simple salting out procedure for extracting DNA from human nucleated cells
Miller, S. A., Dykes, D. D., & Polesky, H. F. (1988) · Nucleic Acids Research · doi:10.1093/nar/16.3.1215 · Cited by 20,341
Sonic hedgehog mediates the polarizing activity of the ZPA
Riddle, R. D., Johnson, R. L., Laufer, E., & Tabin, C. J. (1993) · Cell · doi:10.1016/0092-8674(93)90626-2 · Cited by 2,285
Echelard, Y., Epstein, D. J., St-Jacques, B., Shen, L., Mohler, J., McMahon, J. A., & McMahon, A. P. (1993) · Cell · doi:10.1016/0092-8674(93)90627-3 · Cited by 2,154
Krauss, S. J. K., Concordet, J., & Ingham, P. W. (1993) · Cell · doi:10.1016/0092-8674(93)90628-4 · Cited by 1,072
VISTA : visualizing global DNA sequence alignments of arbitrary length
Mayor, C., Brudno, M., Schwartz, J. R., Poliakov, A., Rubin, E. M., Frazer, K. A., Pachter, L. S., & Dubchak, I. L. (2000) · Bioinformatics · doi:10.1093/bioinformatics/16.11.1046 · Cited by 1,017
Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly
Lettice, L., Horikoshi, T., Heaney, S., van Baren, M. V., van der Linde, H. C., Breedveld, G., Joosse, M., Akarsu, N., Oostra, B., Endo, N., et al. (2002) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.112212199 · Cited by 501
Self-citationThe regulation of myogenin gene expression during the embryonic development of the mouse.Preprint
Yee, S., & Rigby, P. W. J. (1993) · Genes & Development · doi:10.1101/gad.7.7a.1277 · Cited by 423
Selective agenesis of the dorsal pancreas in mice lacking homeobox gene Hlxb9
Li, H., Arber, S., Jessell, T. M., & Edlund, H. (1999) · Nature Genetics · doi:10.1038/12669 · Cited by 377
Position effect in human genetic disease
Kleinjan, D. A. (1998) · Human Molecular Genetics · doi:10.1093/hmg/7.10.1611 · Cited by 370
Research works printed but not linked: 1
- Sanders, J.W. Jr and Gasseling, M.T. (1968) Ectodermal-mesenchymal interactions in the origin of limb symmetry. In Fleischmajar, R. and Billingham, R.F. (eds), Ectodermal-Mesenchymal Interactions. Williams and Wilkins, Baltimore, MD, pp. 78-97.
Cited by
Sorted by citations
GREAT improves functional interpretation of cis-regulatory regions
McLean, C. Y., Bristor, D., Hiller, M., Clarke, S. L., Schaar, B. T., Lowe, C. B., Wenger, A. M., & Bejerano, G. (2010) · Nature Biotechnology · doi:10.1038/nbt.1630 · Cited by 4,502
Three-dimensional Epigenome Statistical Model: Genome-wide Chromatin Looping Prediction
Bkhetan, Z. A., & Plewczyński, D. (2018) · Scientific Reports · doi:10.1038/s41598-018-23276-8 · Cited by 1,672
Transcriptional enhancers: from properties to genome-wide predictions
Shlyueva, D., Stampfel, G., & Stark, A. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3682 · Cited by 1,356
GeneHancer: genome-wide integration of enhancers and target genes in GeneCards
Fishilevich, S., Nudel, R., Rappaport, N., Hadar, R., Plaschkes, I., Stein, T. I., Rosen, N., Kohn, A., Twik, M., Safran, M., et al. (2017) · Database · doi:10.1093/database/bax028 · Cited by 1,270
Hedgehog: functions and mechanisms
Varjosalo, M., & Taipale, J. (2008) · Genes & Development · doi:10.1101/gad.1693608 · Cited by 1,217
Metadata
- Authors
- Lettice, L. A.
- Affiliations
- Western General Hospital (GB)
- Corresponding author
- Lettice, L. A.
- ORCID
- Lettice, L. A.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2003-07-15
- Volume
- 12
- Issue
- 14
- Pages
- 1725-1735
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2145144631
- Cited by
- 1,164
- References
- 35
- Citations by year
- 2026: 26 · 2025: 40 · 2024: 50 · 2023: 58 · 2022: 66 · 2021: 78 · 2020: 52 · 2019: 49 · 2018: 50 · 2017: 50 · 2016: 64 · 2015: 56 · 2014: 78 · 2013: 64 · 2012: 60
- FWCI
- 26.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Lirias (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Keywords
- Sonic hedgehog, preaxial polydactyly, limb bud, fin development, zirconium, LMBR1, point mutations, congenital limb anomalies, chromosome 7q36
- MeSH terms
- Zona Pellucida Glycoproteins, Animals, Base Sequence, Chromosomes, Human, Pair 7, Egg Proteins, Enhancer Elements, Genetic, Extremities, Female, Humans, Male, Membrane Glycoproteins, Membrane Proteins, Molecular Sequence Data, Pedigree, Receptors, Cell Surface, Trans-Activators, Polydactyly, Takifugu, Mice, Hedgehog Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
