Gastrointestinal dysfunction in autism displayed by altered motility and achalasia in Foxp1 ^+/− mice

Abstract

Gastrointestinal dysfunctions in individuals with autism spectrum disorder are poorly understood, although they are common among this group of patients. FOXP1 haploinsufficiency is characterized by autistic behavior, language impairment, and intellectual disability, but feeding difficulties and gastrointestinal problems have also been reported. Whether these are primary impairments, the result of altered eating behavior, or side effects of psychotropic medication remains unclear. To address this question, we investigated Foxp1+/− mice reflecting FOXP1 haploinsufficiency. These animals show decreased body weight and altered feeding behavior with reduced food and water intake. A pronounced muscular atrophy was detected in the esophagus and colon, caused by reduced muscle cell proliferation. Nitric oxide-induced relaxation of the lower esophageal sphincter was impaired and achalasia was confirmed in vivo by manometry. Foxp1 targets (Nexn, Rbms3, and Wls) identified in the brain were dysregulated in the adult Foxp1+/− esophagus. Total gastrointestinal transit was significantly prolonged due to impaired colonic contractility. Our results have uncovered a previously unknown dysfunction (achalasia and impaired gut motility) that explains the gastrointestinal disturbances in patients with FOXP1 syndrome, with potential wider relevance for autism.

GWAS of peptic ulcer disease implicates Helicobacter pylori infection, other gastrointestinal disorders and depression

“…For PG + M, two of the significantly associated SNPs, 19:18793695 and rs13097265, have been previously linked to Barrett’s esophagus and esophageal adenocarcinoma 82 (Supplementary Table 4 ). rs13097265 is located ~60 kb from the FOXP1 gene, and recently a mouse study 83 has shown that Foxp1 protein is expressed in all layers of the murine GI tract (including the myenteric plexus, which is part of the enteric nervous system and regulates gut peristalsis and transit). Altered motility and achalasia has been observed in Foxp1 +/− mice.…”

Coupling of autism genes to tissue-wide expression and dysfunction of synapse, calcium signalling and transcriptional regulation

“…Amongst the results we found enrichment for neuromuscular and cardiac function in STRING analysis (S9-20). Some animal models such as FOXP1 , SHANK3 , NOS1 and CHD8 [ 74 , 92 , 94 , 96 , 97 ] have been developed for functional analysis of ASD candidate genes in the gastrointestinal system, which indicates that ASD genes may play an important role in this organ [ 95 ], and yet most research have been mainly focused on the brain in both human and animal models. A greater utilisation of the animal models to explore other systems such as the cardiac and gastrointestinal systems would be welcome.…”

Characterization of a gene-trap knockout mouse model ofScn2aencoding voltage-gated sodium channel Nav1.2

“…Our Scn2a gtKO/gtKO mice had a similar ~15% reduced body weight compared to WT throughout life, but close to 80% of Scn2a gtKO/gtKO mice survive to adulthood. Another mouse model of neurodevelopmental disorder, Foxp1 -/-, also has failure to thrive at weaning unless a soft, highcalorie diet is provided [36] which we similarly provided a gel-based high-calorie food source. The combined phenomenon of failure to thrive in adolescence and overeating in adulthood in humans is also evident in Prader-Willi syndrome [37].…”