Abstract
Mutations in the gene encoding the immunoglobulin-superfamily member cell adhesion molecule contactin1 (CNTN1) cause lethal congenital myopathy in human patients and neurodevelopmental phenotypes in knockout mice. Whether the mutant mice provide an accurate model of the human disease is unclear; resolving this will require additional functional tests of the neuromuscular system and examination of Cntn1 mutations on different genetic backgrounds that may influence the phenotype. Toward these ends, we have analyzed a new, spontaneous mutation in the mouse Cntn1 gene that arose in a BALB/c genetic background. The overt phenotype is very similar to the knockout of Cntn1, with affected animals having reduced body weight, a failure to thrive, locomotor abnormalities, and a lifespan of 2–3 weeks. Mice homozygous for the new allele have CNTN1 protein undetectable by western blotting, suggesting that it is a null or very severe hypomorph. In an analysis of neuromuscular function, neuromuscular junctions had normal morphology, consistent with previous studies in knockout mice, and the muscles were able to generate appropriate force when normalized for their reduced size in late stage animals. Therefore, the Cntn1 mutant mice do not show evidence for a myopathy, but instead the phenotype is likely to be caused by dysfunction in the nervous system. Given the similarity of CNTN1 to other Ig-superfamily proteins such as DSCAMs, we also characterized the expression and localization of Cntn1 in the retinas of mutant mice for developmental defects. Despite widespread expression, no anomalies in retinal anatomy were detected histologically or using a battery of cell-type specific antibodies. We therefore conclude that the phenotype of the Cntn1 mice arises from dysfunction in the brain, spinal cord or peripheral nervous system, and is similar in either a BALB/c or B6;129;Black Swiss background, raising a possible discordance between the mouse and human phenotypes resulting from Cntn1 mutations.
Highlights
This paper reports a spontaneous mutation in the mouse contactin 1 (Cntn1) gene (MGI: 105980)
We have identified a new, spontaneous mutation in BALB/c mice that maps to Chromosome 15 and results in a null allele of Cntn1
Neuromuscular junctions and muscle in the homozygous animals are anatomically normal, and an examination of the retina for other neurodevelopmental phenotypes did not reveal any defects. These results indicate that the loss of Cntn1 causes a severe and early onset phenotype that is consistent across multiple genetic backgrounds, but that the phenotype in mice differs from human Compton-North congenital myopathy in the backgrounds studied to date
Summary
This paper reports a spontaneous mutation in the mouse contactin 1 (Cntn1) gene (MGI: 105980). CNTN1 interacts with several extracellular proteins, including other Ig-domain proteins, tenascins, phosphacan, and contactin-associated proteins (Casprs) [4,8,9,10,11,12,13,14]. There is a secondary loss of syntrophin and dystrobrevin immunoreactivity from neuromuscular junctions (NMJs) of affected individuals [16]. This condition was mapped to Chromosome 12, and a frame shift mutation in CNTN1 introducing a premature stop codon (S291fsX296) was identified by sequencing candidate genes within the genetic interval. Consistent with the disease presentation, CNTN1 is found at NMJs in both humans and mice [15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
