ArticleGastroenterology2015
Mutations in RAD21 disrupt regulation of APOB in patients with chronic intestinal pseudo-obstruction.
Article in Gastroenterology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 81 citations in OpenAlex.
- Phenotypic Spectrum in Three Romanian Patients with 8q23-q24 Deletions.International journal of molecular sciences · 2026Article
- Co-Occurrence ofInternational journal of molecular sciences · 2025Article
- Chronic atrial and intestinal dysrythmia syndrome: A late-onset intestinal pseudo-obstruction and cardiac dysfunction due to an SGO1 mutation.JPGN reports · 2025Article
- Genomic stress in diseases stemming from defects in the second brain.Neurogastroenterology and motility · 2025Review
- Phenotype and genotype in hereditary chronic intestinal pseudo-obstruction with small intestine involvement.Frontiers in medicine · 2025Review
- Cutting-edge regenerative therapy for Hirschsprung disease and its allied disorders.Surgery today · 2024Review
- Enhancer-promoter specificity in gene transcription: molecular mechanisms and disease associations.Experimental & molecular medicine · 2024Review
- Genetic regulation of enteric nervous system development in zebrafish.Biochemical Society transactions · 2024Review
- NIPBL-mediated RAD21 facilitates tumorigenicity by the PI3K pathway in non-small-cell lung cancer.Communications biology · 2024Article
- Article
- Multi-disciplinary Insights from the First European Forum on Visceral Myopathy 2022 Meeting.Digestive diseases and sciences · 2023Review
- Enteric Neuromyopathies: Highlights on Genetic Mechanisms Underlying Chronic Intestinal Pseudo-Obstruction.Biomolecules · 2022Review
- Pseudoileus caused by primary visceral myopathy in a Han Chinese patient with a rareWorld journal of clinical cases · 2022Article
- Smooth muscle motility disorder phenotypes: A systematic review of cases associated with seven pathogenic genes (Intractable & rare diseases research · 2022Review
- Comment to the Description of a Novel Cohesinopathy in Chronic Intestinal Pseudo Obstruction.Journal of neurogastroenterology and motility · 2022Article
- Review
- Article
- Novel understanding on genetic mechanisms of enteric neuropathies leading to severe gut dysmotility.European journal of histochemistry : EJH · 2021Review
- Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans.The Journal of clinical investigation · 2021Article
- Autozygosity-driven genetic diagnosis in consanguineous families from Italy and the Greater Middle East.Human genetics · 2020Article
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Authors and funding
26 authors at 8 institutions in 4 countries.
Funding
Abstract
BACKGROUND &
aimsChronic intestinal pseudo-obstruction (CIPO) is characterized by severe intestinal dysmotility that mimics a mechanical subocclusion with no evidence of gut obstruction. We searched for genetic variants associated with CIPO to increase our understanding of its pathogenesis and to identify potential biomarkers.
methodsWe performed whole-exome sequencing of genomic DNA from patients with familial CIPO syndrome. Blood and lymphoblastoid cells were collected from patients and controls (individuals without CIPO); levels of messenger RNA (mRNA) and proteins were analyzed by quantitative reverse-transcription polymerase chain reaction, immunoblot, and mobility shift assays. Complementary DNAs were transfected into HEK293 cells. Expression of rad21 was suppressed in zebrafish embryos using a splice-blocking morpholino (rad21a). Gut tissues were collected and analyzed.
resultsWe identified a homozygous mutation (p.622, encodes Ala>Thr) in RAD21 in patients from a consanguineous family with CIPO. Expression of RUNX1, a target of RAD21, was reduced in cells from patients with CIPO compared with controls. In zebrafish, suppression of rad21a reduced expression of runx1; this phenotype was corrected by injection of human RAD21 mRNA, but not with the mRNA from the mutated p.622 allele. rad21a Morpholino zebrafish had delayed intestinal transit and greatly reduced numbers of enteric neurons, similar to patients with CIPO. This defect was greater in zebrafish with suppressed expression of ret and rad21, indicating their interaction in the regulation of gut neurogenesis. The promoter region of APOB bound RAD21 but not RAD21 p.622 Ala>Thr; expression of wild-type RAD21 in HEK293 cells repressed expression of APOB, compared with control vector. The gut-specific isoform of APOB (APOB48) is overexpressed in sera from patients with CIPO who carry the RAD21 mutation. APOB48 also is overexpressed in sporadic CIPO in sera and gut biopsy specimens.
conclusionsSome patients with CIPO carry mutations in RAD21 that disrupt the ability of its product to regulate genes such as RUNX1 and APOB. Reduced expression of rad21 in zebrafish, and dysregulation of these target genes, disrupts intestinal transit and the development of enteric neurons.
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