Respiratory and neurobehavioural characteristics of a murine model of congenital myotonic dystrophy type 1

Abstract

Introduction: Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease caused by CTG repeats in the myotonin-protein kinase. Transcribed mRNA accumulation leads to protein synthesis perturbation and multisystem symptoms. Phenotype severity is correlated to expansion size and is most severe in the congenital form with hypotonia, respiratory failure, mental retardation and high mortality. Aims: To characterize the respiratory and neurobehavioural phenotypes of a mouse model of DM1 with large CTG expansion (>1500 repeats, DMSXL). Methods: Weight and temperature were recorded daily in wild-type, heterozygous and homozygous DMSXL pups from birth to postnatal day 30 (P30). Breathing variables and apnoea duration were measured using whole-body flow barometric plethysmography in air and in response to hypercapnia (8% CO 2 ) and hypoxia (10% O 2 ). Motor development was analysed using righting, cliff avoidance and negative geotaxis tests from P3 to P15 and gait quality assessment from P2 to P30. Results: Weight growth was significantly delayed in DMSXL mice, compared to WT mice. Morphological abnormalities were occasionally present. DMSXL showed significantly longer apnoea duration at P1 and P8. Otherwise breathing variables were normal. Righting and cliff avoidance reflexes were delayed; gait quality was significantly lower compared to controls. Conclusion: DMSXL mice display key features of DM1 and may serve as a model to analyse pathophysiological processes and test treatments.