Evidence map›Paper›PMID 25954033›Full record

ArticleHuman molecular genetics2015

DLX4 is associated with orofacial clefting and abnormal jaw development.

Di Wu, Shyamali Mandal, Alex Choi, August Anderson, Michaela Prochazkova, Hazel Perry, Vera L Gil-Da-Silva-Lopes, Richard Lao, Eunice Wan, Paul Ling-Fung Tang and 4 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.

0numbers the graph read from it
0cells of the map it votes in
19citing papers in PubMed
3.2field-weighted citation impact, top 8% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

19 citing papers in PubMed, 59 citations in OpenAlex.

  1. Review
  2. A zebrafish model ofFrontiers in cell and developmental biology · 2025
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  3. Cells · 2022
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  10. Cancers · 2021
    Review
  11. Article
  12. Article
  13. Review
  14. Review
  15. Article
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  17. Article
  18. Zebrafish models of orofacial clefts.Developmental dynamics : an official publication of the American Association of Anatomists · 2017
    Review
  19. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors at 3 institutions in 3 countries.

Di WuDepartment of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
Shyamali MandalDepartment of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
Alex ChoiDepartment of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
August AndersonDepartment of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
Michaela ProchazkovaDivision of Craniofacial Anomalies, Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA, USA, Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the ASCR, v. v.i., Prague, Czech Republic, Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94114, USA.
Hazel PerryDivision of Craniofacial Anomalies, Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA, USA.
Vera L Gil-Da-Silva-LopesDepartment of Medical Genetics, University of Campinas, São Paulo, Brazil.
Richard LaoCardiovascular Research Institute, University of California San Francisco, San Francisco, USA and.
Eunice WanCardiovascular Research Institute, University of California San Francisco, San Francisco, USA and.
Paul Ling-Fung TangCardiovascular Research Institute, University of California San Francisco, San Francisco, USA and.
Pui-yan KwokCardiovascular Research Institute, University of California San Francisco, San Francisco, USA and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
Ophir KleinDepartment of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA, Division of Craniofacial Anomalies, Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA, USA, Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA, Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94114, USA.
Bian ZhuanKey Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, China.
Anne M SlavotinekDepartment of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA, Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA, slavotia@ucsf.edu.
University of California, San Francisco · USUniversidade Estadual de Campinas (UNICAMP) · BRWuhan University · CN

Funding

The role of Bmi1 in regulation of dental stem cellsR01DE021420 · NIDCR · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KLEIN, OPHIR D · 2011 to 2015
$2.0M
Gene Discovery in Human Anopthalmia/MicropthalmiaR21EY022779 · NEI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI SLAVOTINEK, ANNE M. · 2012 to 2013
$421k
Anopthalmia Spectrum DisordersR21EY019999 · NEI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI SLAVOTINEK, ANNE M. · 2010 to 2011
$417k
NEI NIH HHS 1R21 EY022779-01NEI NIH HHS EY019999-01NEI NIH HHS R21 EY019999NEI NIH HHS R21 EY022779NIDCR NIH HHS R01 DE021420NIDCR NIH HHS R01-DE021420
6 · The paper itself

Abstract

Cleft lip and/or palate (CL/P) are common structural birth defects in humans. We used exome sequencing to study a patient with bilateral CL/P and identified a single nucleotide deletion in the patient and her similarly affected son—c.546_546delG, predicting p.Gln183Argfs*57 in the Distal-less 4 (DLX4) gene. The sequence variant was absent from databases, predicted to be deleterious and was verified by Sanger sequencing. In mammals, there are three Dlx homeobox clusters with closely located gene pairs (Dlx1/Dlx2, Dlx3/Dlx4, Dlx5/Dlx6). In situ hybridization showed that Dlx4 was expressed in the mesenchyme of the murine palatal shelves at E12.5, prior to palate closure. Wild-type human DLX4, but not mutant DLX4_c.546delG, could activate two murine Dlx conserved regulatory elements, implying that the mutation caused haploinsufficiency. We showed that reduced DLX4 expression after short interfering RNA treatment in a human cell line resulted in significant up-regulation of DLX3, DLX5 and DLX6, with reduced expression of DLX2 and significant up-regulation of BMP4, although the increased BMP4 expression was demonstrated only in HeLa cells. We used antisense morpholino oligonucleotides to target the orthologous Danio rerio gene, dlx4b, and found reduced cranial size and abnormal cartilaginous elements. We sequenced DLX4 in 155 patients with non-syndromic CL/P and CP, but observed no sequence variants. From the published literature, Dlx1/Dlx2 double homozygous null mice and Dlx5 homozygous null mice both have clefts of the secondary palate. This first finding of a DLX4 mutation in a family with CL/P establishes DLX4 as a potential cause of human clefts.

Indexed as

AnimalsBone Morphogenetic Protein 4BrainCleft LipCleft PalateExomeGene Expression Regulation, DevelopmentalHeLa CellsHigh-Throughput Nucleotide SequencingHomeodomain ProteinsHumansJaw AbnormalitiesMesodermMiceMice, KnockoutMorpholinosBone Morphogenetic Protein 4dlx3b protein, zebrafishDLX4 protein, humanHomeodomain ProteinsMorpholinosTranscription FactorsZebrafish Proteins

Identifiers

PMID25954033
PMCPMC4492397
OpenAlexW1893508223

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.