| Primary Identifier | MGI:1856216 | Allele Type | Spontaneous |
| Gene | Pmp22 | Inheritance Mode | Dominant |
| Strain of Origin | Not Specified | Is Recombinase | false |
| Is Wild Type | false |
| description | The trembler phenotype is caused by a mutation that arose spontaneously at the Institute of Animal Genetics, Edinburgh (J:13038)). Mortality of heterozygotes is high at 3 to 4 weeks of age but can be improved if moist food is provided within easy reach during this critical period. Females breed normally, but males are frequently sterile. Homozygotes cannot be distinguished from heterozygotes (J:7222). Affected animals are recognizable at 9 to 10 days old by a rapid tremor which remains throughout life, a tendency to convulsions during the first 3 weeks, and spasticity in the muscles of the lower back and limbs. No pathology is found in the CNS or in the dorsal root ganglia. Not surprisingly, cholesterol and cholesterol synthesis precursors which are reduced in the CNS demyelinating mutations Mbpshi and Qk, are not reduced in Pmp22Tr. However, in the PNS, cholesterol levels are reduced to a much greater extent in Pmp22Tr than in Qk and Mbpshi, which have little effect on PNS myelin (J:9907). PNS myelin sheaths in Pmp22Tr mice are thin or absent, and there is a marked deficiency of large myelinated axons. Myelination is delayed, many myelin sheaths are uncompacted, and much of the myelin degenerates (J:5750, J:5746). Although homozygotes and heterozygotes have similar behavioral phenotypes, myelin in heterozygotes is reduced by 50%, while in homozygotes the reduction is 90% (J:2357). Schwann cells proliferate, digest the myelin debris, and engage in remyelination (J:11943), the time course of Schwann cell proliferation being accelerated in trembler mice as compared to wild-type (J:1032). These processes lead to the formation of "onion bulb" axons, surrounded by Schwann cell cytoplasm and by layers of Schwann cell basement membrane (J:11943). At the junction of the spinal cord and ventral root, some of the myelinated fibers of the spinal cord show the same type of abnormality found in ventral roots and peripheral nerves (J:5806). There is marked reduction in motor conduction velocities of the peripheral nerves (J:5612). Transplantation experiments with sciatic nerves of wild-type and trembler mice have shown that the defect caused by Pmp22Tr resides in the Schwann cells, not in the nerve cells (J:5746). The stability of axonal microtubule cytoskeleton is decreased in trembler mice, with altered composition of associated proteins (J:21886). Cultures of dorsal root ganglia from 15- to 16-day Pmp22Tr/+ embryos develop abnormal myelination resembling that in adults of the same genotype (J:26983). Alterations in skeletal muscle (J:6775) and in lipids and proteins of peripheral myelin (J:26982, J:7749, J:7775) have been described. |
| molecularNote | Sequence analysis of cDNA shows a G-to-A transition at coding nucleotide 449 resulting in substitution of glycine with aspartic acid at position 150 (p.G150D). |
