Disease relevance of Pmp22

• Mice carrying one functional copy of Pmp22 are less affected but they also exhibit focal tomacula comparable to the morphological features in hereditary neuropathy with liability to pressure palsies (HNPP) [1].
• The natural mouse mutants Trembler and Trembler-J contain a missense mutation in different hydrophobic domains of PMP22, resulting in demyelination and Schwann cell proliferation [2].
• Overloaded endoplasmic reticulum-Golgi compartments, a possible pathomechanism of peripheral neuropathies caused by mutations of the peripheral myelin protein PMP22 [3].
• These combined findings are reminiscent of the disease progression in HNPP and offer a possible explanation about why some HNPP patients develop a chronic motor and sensory neuropathy later in life that resembles demyelinating forms of Charcot-Marie-Tooth disease by both morphological and clinical criteria [4].
• This is evident from the genetic disease mechanisms in Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) as well as transgenic animals with altered PMP22 gene dosage [5].

High impact information on Pmp22

• These findings suggest that Tr beta controls the maturation of auditory function but not morphogenesis of the cochlea [6].
• Thrb-/- mice provide a model for the human endocrine disorder of resistance to thyroid hormone (RTH), which is typically associated with dominant mutations in Tr beta [6].
• Peripheral myelin protein PMP22 has been suggested to have a role in peripheral nerve myelination and cell proliferation [1].
• Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that causes episodes of focal demyelinating neuropathy following minor trauma to peripheral nerves [7].
• We assign the HNPP locus to chromosome 17p11.2 and demonstrate the presence of a large interstitial deletion associated with this disorder in three unrelated pedigrees [7].

Chemical compound and disease context of Pmp22

• Peripheral myelin protein 22 (PMP22) is a tetraspan glycoprotein whose misexpression is associated with a family of hereditary peripheral neuropathies [8].
• The increased in vivo sulfate and galactose incorporation into non-lipidic material couild reflect the overproduction of endoneurial and perineurial connective tissue, whereas the high turnover rate of sulfatides could be correlated with intense demyelination and remyelination observed in Trembler PNS [9].

Biological context of Pmp22

• 2. A related disorder in the mouse, trembler (Tr), maps to mouse chromosome 11 which has syntenic homology to human chromosome 17p [10].
• Recently, the peripheral myelin gene Pmp-22 was found to carry a point mutation in Tr mice [11].
• Comparison of Trembler and Trembler-J mouse phenotypes: varying severity of peripheral hypomyelination [12].
• (putative TrJ/+) animals to each other, and not with matings of putative TrJ/+ X +/+, some offspring, putative homozygotes, TrJ/TrJ, were more severely affected behaviorally and had more extreme peripheral hypomyelination than any Tr/? animals [12].
• Aberrant protein trafficking in Trembler suggests a disease mechanism for hereditary human peripheral neuropathies [13].

Anatomical context of Pmp22

• We investigated the intracellular transport of wild-type PMP22 and its TrJ and Tr mutant forms in Schwann cells and in a non-neuronal cell line [3].
• In agreement with the findings in vitro, Tr protein was not detectable in myelin of Tr/0 mice [13].
• In spite of their differences, Tr/?, putative TrJ/+, and putative TrJ/TrJ animals shared a failure or marked delay of Schwann cells to progress from the stage of axonal ensheathment in a 1:1 relationship to myelination [12].
• Trembler (Tr) is an autosomal dominant mutation which produces hypomyelination and demyelination in the mouse peripheral nervous system [12].
• Another result was that PO levels are reduced in the trembler mouse sciatic nerve [14].

Associations of Pmp22 with chemical compounds

• Dietary ascorbic acid prevented dysmyelination and premature death in a Pmp22 transgenic mouse line [15].
• Developmental expression of the P0 glycoprotein and basic protein mRNAs in normal and trembler mutant mice [16].
• The Trembler mouse (Tr) suffers from a dominantly inherited autosomal mutation (glycine to aspartic acid. G150D) affecting the PMP22 gene, which results in an abnormal myelination of the peripheral nervous system [17].
• Lectin binding showed that, in contrast to brain in which most glycoproteins contain primarily alpha 2-3 linked sialic acid, most glycoproteins of both control and trembler nerve contained primarily alpha 2-6 linked sialic acid [18].
• The possibility of the treatment of globoid cell leucodystrophy in the twitcher mouse by enzyme replacement was investigated using nerve grafts from affected animals into trembler hosts [19].

Regulatory relationships of Pmp22

• MBP species are at most 4% of the control in the 10- to 12-d-old Trembler mice, whereas they were not detectable in adult nerves [20].
• A significant increase of the Ca2+-stimulated ATPase activity promoted a drastic loss in the efficiency of the calcium pumping system of the membrane purified from trembler mice [21].

Other interactions of Pmp22

• We found that TrJ was tightly linked on chromosome 11 to vestigial tail, vt, as is Tr [12].
• Myelin-associated glycoprotein and other proteins in Trembler mice [22].
• The timing and rate of accumulation of MBP were normal in Trembler [23].
• Schwann cells from trembler mice, which lack PNS myelin, had significantly decreased TPO1 expression and an altered localization pattern, suggesting that TPO1 is a functional myelin membrane protein [24].
• At days 12 and 40, the P0 mRNA proportion measured in Trembler sciatic nerves represents only 40% and 7%, respectively, of the proportion measured in control littermates [16].

Analytical, diagnostic and therapeutic context of Pmp22

• Development and applications of a solid-phase radioimmunoassay for the PO protein of peripheral myelin [14].
• The Tr mouse represents an animal model for the human hereditary neuropathy, Charcot-Marie-Tooth disease [17].
• Using the Northern blot technique, we investigated the steady-state levels of mRNA encoding myelin protein genes in 8-day-old normal and trembler brains [25].
• Immunoblotting analysis did not reveal an increased apparent Mr for MAG, as has been observed in quaking and trembler mice [26].
• Using immunological techniques, we show that, as early as postnatal day 8, the P0 content of mice homozygous and heterozygous for the Trembler mutation, represent respectively one tenth and half of the normal values [27].

References