Evidence map›Paper›PMID 25839327›Full record

ArticleAmerican journal of human genetics2015

Functional loss of semaphorin 3C and/or semaphorin 3D and their epistatic interaction with ret are critical to Hirschsprung disease liability.

Qian Jiang, Stacey Arnold, Tiffany Heanue, Krishna Praneeth Kilambi, Betty Doan, Ashish Kapoor, Albee Yun Ling, Maria X Sosa, Moltu Guy, Qingguang Jiang and 15 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
72citing papers in PubMed, 1 pooled it
14.2field-weighted citation impact, top 1% 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

72 citing papers in PubMed, 1 synthesis or guideline pooled it, 147 citations in OpenAlex.

  1. Pooled it
  2. Trial
  3. Observational
  4. Enteric glia, neuropeptides, and Parkinson's: impacts of calcitonin gene-related peptide on gut alpha synuclein.American journal of physiology. Gastrointestinal and liver physiology · 2026
    Article
  5. Review
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  9. Article
  10. Article
  11. Article
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  13. Article
  14. Genetics of Hirschsprung's disease.Pediatric surgery international · 2023
    Review
  15. Article
  16. Article
  17. Article
  18. Article
  19. Article
  20. Association betweenTranslational pediatrics · 2022
    Article

12 more citing papers are in PubMed but not listed here.

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

25 authors at 8 institutions in 7 countries.

Qian JiangMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Medical Genetics, Capital Institute of Pediatrics, Beijing 100020, China.
Stacey ArnoldMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Tiffany HeanueDivision of Molecular Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Krishna Praneeth KilambiDepartment of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Betty DoanMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Ashish KapoorMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Albee Yun LingMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Maria X SosaMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Moltu GuyMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Qingguang JiangDepartment of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Grzegorz BurzynskiMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Kristen WestMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Seneca BesslingMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Paola GriseriU.O.C. Genetica Medica, Istituto Gaslini, 16147 Genova, Italy.
Jeanne AmielINSERM UMR 1163, Laboratory of Embryology and Genetics of Congenital Malformations, 75015 Paris, France; Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, 75015 Paris, France.
Raquel M FernandezDepartment of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, 41013 Seville, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), 41013 Seville, Spain.
Joke B G M VerheijDepartment of Medical Genetics, University of Groningen, Groningen 9700, Germany.
Robert M W HofstraDepartment of Clinical Genetics, University of Rotterdam, Erasmus Medical Center, 3015 CE Rotterdam, the Netherlands; Neural Development and Gastroenterology Units, UCL Institute of Child Health, London WC1 NEH, UK.
Salud BorregoDepartment of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, 41013 Seville, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), 41013 Seville, Spain.
Stanislas LyonnetINSERM UMR 1163, Laboratory of Embryology and Genetics of Congenital Malformations, 75015 Paris, France; Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, 75015 Paris, France.
Isabella CeccheriniU.O.C. Genetica Medica, Istituto Gaslini, 16147 Genova, Italy.
Jeffrey J GrayDepartment of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Vassilis PachnisDivision of Molecular Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Andrew S McCallionMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Aravinda ChakravartiMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: aravinda@jhmi.edu.
Johns Hopkins University · USJohns Hopkins Medicine · USIstituto Giannina Gaslini · ITUniversidad de Sevilla · ESCapital Institute of Pediatrics · CNErasmus MC · NLSorbonne Paris Cité · FRUniversité Paris Cité · FR

Funding

Genetic Analysis of Hirschsprung Disease - RenewalR01HD028088 · NICHD · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI CHAKRAVARTI, ARAVINDA · 1991 to 2024
$6.2M
Genetic Analysis of Hirschsprung DiseaseR37HD028088 · NICHD · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI CHAKRAVARTI, ARAVINDA · 2010 to 2019
$6.2M
Development of a Neuronal Regulatory LexiconR01NS062972 · NINDS · JOHNS HOPKINS UNIVERSITY · PI MCCALLION, ANDREW S · 2009 to 2018
$4.1M
Prediction of the Structure of Therapeutic Antibodies with their AntigensR01GM078221 · NIGMS · JOHNS HOPKINS UNIVERSITY · PI GRAY, JEFFREY J · 2006 to 2020
$4.0M
Genetics of Disease Gene RegulationR01GM071648 · NIGMS · JOHNS HOPKINS UNIVERSITY · PI MCCALLION, ANDREW S · 2006 to 2010
$1.6M
Medical Research Council MC_U117537087NICHD NIH HHS HD28088NICHD NIH HHS R01 HD028088NICHD NIH HHS R37 HD028088NIGMS NIH HHS GM71648NIGMS NIH HHS R01 GM071648NIGMS NIH HHS R01 GM078221NINDS NIH HHS R01 NS062972
6 · The paper itself

Abstract

Innervation of the gut is segmentally lost in Hirschsprung disease (HSCR), a consequence of cell-autonomous and non-autonomous defects in enteric neuronal cell differentiation, proliferation, migration, or survival. Rare, high-penetrance coding variants and common, low-penetrance non-coding variants in 13 genes are known to underlie HSCR risk, with the most frequent variants in the ret proto-oncogene (RET). We used a genome-wide association (220 trios) and replication (429 trios) study to reveal a second non-coding variant distal to RET and a non-coding allele on chromosome 7 within the class 3 Semaphorin gene cluster. Analysis in Ret wild-type and Ret-null mice demonstrates specific expression of Sema3a, Sema3c, and Sema3d in the enteric nervous system (ENS). In zebrafish embryos, sema3 knockdowns show reduction of migratory ENS precursors with complete ablation under conjoint ret loss of function. Seven candidate receptors of Sema3 proteins are also expressed within the mouse ENS and their expression is also lost in the ENS of Ret-null embryos. Sequencing of SEMA3A, SEMA3C, and SEMA3D in 254 HSCR-affected subjects followed by in silico protein structure modeling and functional analyses identified five disease-associated alleles with loss-of-function defects in semaphorin dimerization and binding to their cognate neuropilin and plexin receptors. Thus, semaphorin 3C/3D signaling is an evolutionarily conserved regulator of ENS development whose dys-regulation is a cause of enteric aganglionosis.

Indexed as

Genetic VariationAnimalsBase SequenceEpistasis, GeneticGenetic Predisposition to DiseaseGenome-Wide Association StudyHirschsprung DiseaseMiceMolecular Sequence DataProto-Oncogene Proteins c-retSemaphorinsSequence Analysis, DNAProto-Oncogene Proteins c-retRet protein, mouseSema 3D protein, mousesemaphorin 3C protein, mouseSemaphorins

Identifiers

PMID25839327
PMCPMC4385176
OpenAlexW2137657729

What OpenQuestion holds

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Registered trials

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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.