Suter U, Moskow J J, Welcher A A, Snipes G J, Kosaras B, Sidman R L, Buchberg A M, Shooter E M
Department of Neurobiology, Stanford University School of Medicine, CA 94305-5401.
Proc Natl Acad Sci U S A. 1992 May 15;89(10):4382-6. doi: 10.1073/pnas.89.10.4382.
Peripheral myelin protein PMP-22 is a potential growth-regulating myelin protein that is expressed by Schwann cells and predominantly localized in compact peripheral myelin. A point mutation in the Pmp-22 gene of inbred trembler (Tr) mice was identified and proposed to be responsible for the Tr phenotype, which is characterized by paralysis of the limbs as well as tremors and transient seizures. In support of this hypothesis, we now report the fine mapping of the Pmp-22 gene to the immediate vicinity of the Tr locus on mouse chromosome 11. Furthermore, we have found a second point mutation in the Pmp-22 gene of trembler-J (TrJ) mice, which results in the substitution of a leucine residue by a proline residue in the putative first transmembrane region of the PMP-22 polypeptide. Tr and TrJ were previously mapped genetically as possible allelic mutations giving rise to similar, but not identical, phenotypes. This finding is consistent with the discovery of two different mutations in physicochemically similar domains of the PMP-22 protein. Our results strengthen the hypothesis that mutations in the Pmp-22 gene can lead to heterogeneous forms of peripheral neuropathies and offer clues toward possible explanations for the dominant inheritance of these disorders.
外周髓磷脂蛋白PMP - 22是一种潜在的生长调节性髓磷脂蛋白，由施万细胞表达，主要定位于致密的外周髓磷脂中。已在近交系颤抖（Tr）小鼠的Pmp - 22基因中鉴定出一个点突变，并认为该突变是Tr表型的原因，其特征为肢体麻痹以及震颤和短暂性癫痫发作。为支持这一假说，我们现在报告将Pmp - 22基因精细定位到小鼠11号染色体上Tr位点的紧邻区域。此外，我们在颤抖 - J（TrJ）小鼠的Pmp - 22基因中发现了第二个点突变，该突变导致PMP - 22多肽假定的第一个跨膜区域中的一个亮氨酸残基被脯氨酸残基取代。Tr和TrJ先前在遗传学上被定位为可能的等位基因突变，产生相似但不完全相同的表型。这一发现与在PMP - 22蛋白物理化学性质相似的结构域中发现两个不同突变的情况一致。我们的结果强化了Pmp - 22基因突变可导致外周神经病变的异质性形式这一假说，并为这些疾病的显性遗传提供了可能的解释线索。
