Discovering molecular defects of severe gut dysfunction: new abnormalities underlying Chronic Intestinal Pseudo-Obstruction (CIPO)

In Western countries approximately 30% of the general population are affected by unexplained symptoms that are presumed to be of gastrointestinal (GI) origin and are often referred to as "functional". Most of these patients experience transient or mild-to-moderate symptoms to which a coping behaviour may be developed. However, a minority have impairment of digestive function that is so severe to hinder normal feeding and cause severe symptoms, typically chronic abdominal pain, nausea, vomiting, bloating, and severe constipation. These symptoms compromise patients' quality of life, especially when recurrent sub-occlusive episodes, mimicking a mechanical cause in the absence of any lesions obstructing the gut lumen (hence the term intestinal pseudo-obstruction), lead to well-established consequences such as frequent hospitalisation, malnutrition, opioid dependence and harmful and futile surgeries. At this clinically severe end of the spectrum there are patients diagnosed as having a chronic impairment of gut physiology clinically labelled as chronic intestinal pseudo-obstruction (CIPO). This condition can result from abnormalities affecting the neuromuscular component of the gut (mainly the enteric nervous system, ENS) possibly due to an attendant genetic abnormality. We have recently identified in a consanguineous family with CIPO the related genetic mutation of RAD21, a transcription and chromosomal stability factor gene. The present project will be directed to elucidate the molecular abnormalities associated with RAD21 mutation that are linked to CIPO. Broadly, our mission is to provide the patients with an answer to their severe digestive complains, improve the diagnosis and foster the development of effective therapeutic options.