Characterization of gastrointestinal pathologies in the dystonia musculorum mouse model for hereditary sensory and autonomic neuropathy type VI

Abstract

Background Dystonia musculorum (Dstdt) is a murine disease caused by recessive mutations in the dystonin (Dst) gene. Loss of dorsal root ganglion (DRG) sensory neurons, ataxia, and dystonic postures before death by postnatal day 18 (P18) is a hallmark feature. Recently we observed gas accumulation and discoloration in the small intestine and cecum in Dstdt mice by P15. The human disease resulting from dystonin loss‐of‐function, known as hereditary sensory and autonomic neuropathy type VI (HSAN‐VI), has also been associated with gastrointestinal (GI) symptoms including chronic diarrhea and abdominal pain. As neuronal dystonin isoforms are expressed in the GI tract, we hypothesized that dystonin loss‐of‐function in Dstdt‐27J enteric nervous system (ENS) neurons resulted in neurodegeneration associated with the GI abnormalities. Methods We characterized the nature of the GI abnormalities observed in Dstdt mice through histological analysis of the gut, assessing the ENS for signs of neurodegeneration, evaluation of GI motility and absorption, and by profiling the microbiome. Key results Though gut histology, ENS viability, and GI absorption were normal, slowed GI motility, thinning of the colon mucous layer, and reduced microbial richness/evenness were apparent in Dstdt‐27J mice by P15. Parasympathetic GI input showed signs of neurodegeneration, while sympathetic did not. Conclusions & Inferences Dstdt‐27J GI defects are not linked to ENS neurodegeneration, but are likely a result of an imbalance in autonomic control over the gut. Further characterization of HSAN‐VI patient GI symptoms is necessary to determine potential treatments targeting symptom relief.

Sensory-motor circuit is a therapeutic target for dystonia musculorum mice, a model of hereditary sensory and autonomic neuropathy 6

“…Patients with HSAN-VI suffer from autonomic dysfunction and sensory neuropathy (7)(8)(9)(10)(11). Neuronal degeneration in the autonomic nervous system has been reported in dt mice (44,45). We are now investigating the significance of autonomic dysfunctions in dt mice.…”