Abstract
Charcot-Marie-Tooth disease (CMT) is the most common peripheral neuromuscular disorder worldwide. The axonal degeneration in CMT causes distal muscle weakness and atrophy, resulting in gait problems and difficulties with basic motor coordination skills. A mutation in the cytoplasmic dynein heavy chain (DHC) gene was discovered to cause an autosomal dominant form of the disease designated Charcot-Marie-Tooth type 2O disease (CMT2O) in 2011. The mutation is a single amino acid change of histidine into arginine at amino acid 306 (H306R) in DHC. We previously generated a knock-in mouse carrying the corresponding CMT2O mutation (H304R) and examined the heterozygous H304R/+offspring in a variety of motor skills and histological assays. Here we report the initial characterization of the homozygous H304R/R mouse, which is the first homozygous mutant DHC mouse to survive past the neonatal stage. We show that H304R/R mice have significantly more severe disease symptoms than the heterozygous H304R/+mice. The H304R/R mice have significant defects in motor skills, including grip strength, motor coordination, and gait and also related defects in neuromuscular junction architecture. Furthermore, the mice have defects in sensation, another aspect of CMT disease. Our results show that the H304R/+ and H304R/R mice will be important models for studying the onset and progression of both heterozygous and homozygous CMT disease alleles.
Highlights
With new capabilities to screen and identify mutations in affected populations, there has been a rapid identification of mutations within the Dync1h1 gene that appear to be the causative agents in a variety of neurological disorders
In an effort to study the onset and progression of Charcot-Marie-Tooth disease (CMT) type 2 caused by a cytoplasmic dynein mutation, we previously developed a knock-in mouse carrying a H304R mutation in the Dync1h1 cytoplasmic dynein heavy chain gene that corresponds to the histidine 306 to arginine (H306R) mutation in humans[5]
We examined the effect of the H304R mutation in heterozygous H304R/+ mice, which correlates to the autosomal dominant status of the human H306R/+ CharcotMarie-Tooth type 2O disease (CMT2O) mutation
Summary
With new capabilities to screen and identify mutations in affected populations, there has been a rapid identification of mutations within the Dync1h1 gene that appear to be the causative agents in a variety of neurological disorders. The autosomal dominant mutations in Loa (F580Y), Cra (Y1055C), and Swl ([GIVT]1040[A]) mice do not correspond to human mutations as they were generated by mutagenesis and screened for locomotor defects[6,7,8]. Dynein motor molecules in heterozygous mutant animals are expected to contain DHCs in the following ratio: a quarter of the dynein motors will have a DHC dimer with two wild type monomers, a quarter will have a DHC dimer with two mutant monomers, and half will have a DHC dimer containing one wild type and one mutant monomer The presence of these three categories of dynein motors within heterozygous animals may be a part of the basis for disease onset and progression, but certainly complicate the understanding of what an individual mutation may be doing to the population of dynein motor molecules inside cells
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have