These mice carry a spontaneous mutation at the Htra2 locus characterized by a basal ganglia disorder resulting in muscle atrophy, hunched posture, increased imbalance, chorea, dystonia, and progressive akinesis.Read More +
Mice homozygous for the recessive Htra2mnd2 mutation have a basal ganglia disorder initially described as an early onset motor neuron disease. This is first outwardly evident by 21 to 24 days of age as an unsteady gait with extended hind limbs, repetitive movements and episodes of sudden arrests. This progresses to include severe muscle atrophy, hunched posture, increased imbalance, chorea, dystonia, and progressive akinesis. A failure to gain weight becomes evident shortly after the onset of the other symptoms and by 35 days of age wildtype littermates are twice as heavy as the mutants. Body fat is not detectable at necropsy. Both the spleen and the thymus drop from normal weights at 23 days of age to 10% of normal at 30 days of age and the thymic corticomedullary junction is lost. Death usually occurs within two weeks of disease onset, by 40 days of age. The growth retardation is not the primary cause since disease is not delayed by intragastric feeding.
Although the initial assessment of the Htra2mnd2 phenotype described a primary motor neuron disease, it has been characterized subsequently as a basal ganglia disorder. Neurodegeneration is first detected in the striatum around 23 days of age and progresses such that mid-striatum sections at 39 days of age show a loss of approximately 50% of the neurons. Neuronal degeneration that is much less severe is also found after 30 days of age in the N. amygdaloides corticalis, N. subthalamicus, Globus pallidus, claustrum, amygdala, and brain stem, in addition to the motor neuron degeneration found in the spinal cord which led to the initial characterization of motor neuron degeneration. No neurodegeneration is detected in the cerebellum, and myelin staining is normal. Astrogliosis and microgliosis are detected only in the striatum and N. amygdaloides, and progress parallel with neurodegeneration. There is an upregulation of Il1b, Il6, Il10, Il12, Csf1 and Tnfa in the central nervous system, an upregulation of Csf2, Il1b and Tnfa in the lungs, and an upregulation of Il1b and Tnfa in spleen as well. The dying neurons have characteristics consistent with both apoptotic and necrotic death. Transgenic expression of human BCL2 under the control of a neuron-specific enolase promoter fails to prevent disease in Htra2mnd2 homozygotes.
Histochemistry of spinal chords taken from 34-38 day old homozygotes shows that the motoneurons in both the cervical and lumbar regions are swollen, spherical, and show weaker staining with cresyl violet. Abnormal spontaneous activity with fibrillation potentials and positive waves is detected in needle electromyography of hind limb muscles, indicating denervation. However, unlike surgical and other models of denervation, Htra2mnd2 homozygotes do not have an increase in transcription of the acetylcholine receptor alpha subunit in affected muscle. Although motor nerve conduction velocities are normal, indicating normal axon function, the compound muscle action potential amplitudes are less than half of normal.
mnd2 was first identified in the progeny of a transgenic founder. The transgene had been injected into (C3H/HeJ x C57BL/6J)F2 fertilized eggs. The mnd2 mutation was bred away from the transgene through outcrossing to C57BL/6J with progeny testing to identify mnd2 carriers. Carriers were later bred to CAST/Ei and fine mapping of the mnd2 congenic interval showed that this mutation arose in the chromosomal segment from C57BL/6J. More recently this stock was crossed once to C57BL/6J and subsequently crossed once to SJL/J before being intercrossed and then backcrossed 4 times to C57BL/6J. It was then imported into The Jackson Laboratory in February 2005 where it was backcrossed by in vitro fertilization for re-derivation using an N4 heterozygous male and C57BL/6J females. The N5 insipient congenic offspring were then intercrossed.
|Allele Name||motor neuron degeneration 2|
|Gene Symbol and Name||Htra2, HtrA serine peptidase 2|
|Gene Synonym(s)||AI481710; HtrA2; MGCA8; OMI; PARK13; PRSS25; Prss25; Prss25; expressed sequence AI481710; mnd2; mnd2; motor neuron degeneration 2; protease, serine, 25|
|Strain of Origin||C57BL/6J|
|Molecular Note||The mutation in the mnd2 mouse has been identified as an A to T transversion that predicts a Ser276Cys change in the protease domain of the protein. This mutation has no effect on mRNA or protein concentrations. However, enzyme assays reveal that the serine protease activity of this protein is lost.|
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