• A Genetic Cause of Chronic Intestinal Pseudo-obstruction

A Genetic Cause of Chronic Intestinal Pseudo-obstruction

An inherited form of chronic intestinal pseudo-obstruction (CIPO) is caused by mutations in a transcription factor that disrupt the structure and function of enteric innervation, researchers report in the April issue of Gastroenterology.

Elena Bonora et al show that patients with CIPO carry mutations in RAD21 that disrupt the ability of its product to regulate genes including RUNX1 and APOB. Reduced expression of rad21 in zebrafish, and dysregulation of these target genes, disrupts intestinal transit and the development of enteric neurons.

(A) RAD21 belongs to the cohesin complex, which regulates chromosomal replication. RAD21 p.622Thr does not alter SMC1A subunit binding. (B) Wild-type RAD21 promotes RUNX1 and represses APOB expression. RAD21 p.622Thr down-regulates RUNX1 expression, de-represses APOB expression, leading to loss of enteric neurons and hypoganglionosis. Alternative pathways include RET activation, which can lead to APOB overexpression and hypoganglionosis.

(A) RAD21 belongs to the cohesin complex, which regulates chromosomal replication. RAD21 p.622Thr does not alter SMC1A subunit binding. (B) Wild-type RAD21 promotes RUNX1 and represses APOB expression. RAD21 p.622Thr down-regulates RUNX1 expression, de-represses APOB expression, leading to loss of enteric neurons and hypoganglionosis. Alternative pathways include RET activation, which can lead to APOB overexpression and hypoganglionosis.

CIPO is characterized by severe intestinal dysmotility that mimics a mechanical subocclusion, yet there is no evidence of gut obstruction. Patients typically present with severe disease, but the lack of specific markers of CIPO hinder diagnosis. As a result, patients have a poor quality of life and high mortality.

Most patients have sporadic occurrences of CIPO, although X-linked, autosomal-dominant, and recessive forms have been identified. However, it is not clear what specific genetic alterations lead to CIBO.

Bonora et al attempted to identify genetic factors that might cause this disease by whole-exome sequencing analysis of a previously mapped locus in a large consanguineous family with an autosomal-recessive form of CIPO.

They identified a homozygous mutation in RAD21 (p.622, encodes Ala>Thr) in patients from this family.

RAD21 is part of the cohesin complex that controls pairing of sister chromatid pairing and unpairing during cell replication. RAD21 is also a transcription factor required for development, survival, and maintenance of epithelial cells and neurons of the gastrointestinal tract. Mice with heterozygous disruption of Rad21 have gastrointestinal defects after X-ray irradiation.

Bonora et al found that expression of the transcription factor RUNX1, a target of RAD21, was reduced in cells from patients with CIPO compared to patients without CIPO (controls). The authors propose that RUNX1 is required for migration of neuronal progenitors, possibly in the neural crest.

When Bonora et al suppressed expression of rad21a in zebrafish (rad21a morpholinos), this 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 rad21a, indicating their interaction in regulation of gut neurogenesis.

Bonora et al also found that RAD21 bound to the promoter region of APOB to repress its expression. The gut-specific isoform of APOB (APOB48) was overexpressed in sera from patients with CIPO who carry the RAD21 mutation. APOB48 also is overexpressed in sera and intestinal tissues from patients with sporadic CIPO. The authors propose a correlation between level of APOB48 and the degree of neuronal loss or disease severity.

Bonora et al developed a model in which RAD21 functions in the cohesin complex that regulates chromosomal replication in enteric neurons, and as a transcription factor that promotes RUNX1 and represses APOB expression (see figure).

The mutant form of RAD21 disrupts these processes, leading to loss of enteric neurons and hypoganglionosis.

Bonora et al conclude that these findings provide important new information about the pathogenesis of CIPO. Increased levels of APOB48 could serve as a biomarker for this severe disabling gut dysmotility disorder.

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