(13) Examining the Role of MYT1L Loss in Motor Neurons to Drive Hypotonia Observed in MYT1L Neurodevelopmental Syndrome

Background: Hypotonia, or low muscle tone, is a common finding in neonates in the NICU. Genetic causes of hypotonia are found in ~50% of cases where genetic testing is sent. In addition, several genetic causes of neurodevelopmental disorders include hypotonia as a common symptom. However, the neural pathways contributing to hypotonia in these patients are not well understood. The gene Myelin Transcription Factor 1 Like (MYT1L) has been associated with neurodevelopmental disorders (NDD), with MYT1L loss of function now recognized as MYT1L Neurodevelopmental Syndrome. Hallmark features of MYT1L Neurodevelopmental Syndrome include intellectual disability, obesity, speech and motor delay, partially penetrant ADHD and autism, and, importantly here, hypotonia. Recently, we generated the first murine model of Myt1l haploinsufficiency that mirrors a basepair insertion, frameshift mutation found in a local index patient with MYT1L Neurodevelopmental Syndrome. This model recapitulates many clinical phenotypes including motor issues that are consistent with hypotonia such as decreased fore- and hindlimb grip strength, decreased forelimb and hindlimb strength, and reduced ability to maintain balance on an incline.

Objectives: The objective of this study is to examine if knockdown of Myt1l in motor neurons contributes to hypotonia observed in MYT1L Neurodevelopmental Syndrome.

Design/Methods: In the current study, we utilized conditional knockdown of Myt1l in cholinergic neurons including motor neurons to assess whether loss of Myt1l in these neurons contributes to the hypotonia seen in constitutive Myt1l haploinsufficient mice. We tested these mice on several behavior tests of strength and mobility.

Results: Preliminary results show that mice with knockdown of Myt1l in cholinergic neurons may have decreased strength on a grip strength assay but similar scores on other tests of motor strength and endurance as their control littermates.

Conclusions: Thus far, these data suggest that knockdown of Myt1l in motor neurons may partially contribute but not completely explain the hypotonia observed in our MYT1L Neurodevelopmental Syndrome model. Future studies will focus on examining central nervous system pathways associated with hypotonia in this model of genetic liability for neurodevelopmental disorder and hypotonia.