Abstract
Charcot-Marie-Tooth disease (CMT) is a peripheral neuromuscular disorder in which axonal degeneration causes progressive loss of motor and sensory nerve function. The loss of motor nerve function leads to distal muscle weakness and atrophy, resulting in gait problems and difficulties with walking, running, and balance. 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 2 O disease (CMT2O) in 2011. The mutation is a single amino acid change of histidine into arginine at amino acid 306 (H306R) in DHC. In order to understand the onset and progression of CMT2, we generated a knock-in mouse carrying the corresponding CMT2O mutation (H304R/+). We examined H304R/+ mouse cohorts in a 12-month longitudinal study of grip strength, tail suspension, and rotarod assays. H304R/+ mice displayed distal muscle weakness and loss of motor coordination phenotypes consistent with those of individuals with CMT2. Analysis of the gastrocnemius of H304R/+ male mice showed prominent defects in neuromuscular junction (NMJ) morphology including reduced size, branching, and complexity. Based on these results, the H304R/+ mouse will be an important model for uncovering functions of dynein in complex organisms, especially related to CMT onset and progression.
Highlights
Charcot Marie Tooth disease (CMT) is an inherited peripheral neuromuscular disorder in which length dependent axonal degeneration results in progressive loss of motor and sensory nerve function
In 2011, a mutation in the Dync1h1 cytoplasmic dynein heavy chain (DHC) gene was discovered to be the cause of CMT2 disease in four generations of an afflicted family and was designated Charcot Marie Tooth type 2 O disease (CMT2O)[10]
A single amino acid change of histidine at amino acid 306 into arginine (H306R) of the Dync1h1 gene resulted in an autosomal dominant form of CMT2 that included phenotypes such as pes cavus, abnormal gait, lower limb weakness and wasting, learning difficulties, and reduced sensory reception[10]
Summary
Charcot Marie Tooth disease (CMT) is an inherited peripheral neuromuscular disorder in which length dependent axonal degeneration results in progressive loss of motor and sensory nerve function. In 2011, a mutation in the Dync1h1 cytoplasmic dynein heavy chain (DHC) gene was discovered to be the cause of CMT2 disease in four generations of an afflicted family and was designated Charcot Marie Tooth type 2 O disease (CMT2O)[10]. A single amino acid change of histidine at amino acid 306 into arginine (H306R) of the Dync1h1 gene resulted in an autosomal dominant form of CMT2 that included phenotypes such as pes cavus, abnormal gait, lower limb weakness and wasting, learning difficulties, and reduced sensory reception[10]. The identification of a Dync1h1 mutation causing Charcot Marie Tooth type 2 O provides a unique opportunity to directly study the mechanism by which a specific mutation results in the onset and progression of CMT type 2 disease. The heterozygous mutations in dynein that cause CMT2 disease or other neurological disorders do not abolish function but must alter dynein function in some way
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