Different mutations in the same codon of the proteolipid protein gene,PLP, may help in correlating genotype with phenotype in Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2)

Abstract

Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2) comprises a spectrum of diseases that range from severe to quite mild. The reasons for the variation in severity are not obvious, but suggested explanations include the extent of disruption of the transmembrane portion of the proteolipid protein caused by certain amino acid substitutions and interference with the trafficking of the PLP molecule in oligodendrocytes. Four codons in which substitution of more than one amino acid has occurred are available for examination of clinical and potential structural manifestations: Valine165 to either glutamate or glycine, leucine 045 to either proline or arginine, aspartate 202 to asparagine or histidine, and leucine 223 to isoleucine or proline. Three of these mutations, Val165Gly, Leu045Pro, and Leu223Ile have not been described previously in humans. The altered amino acids appear in the A-B loop, C helix, and C-D loop, respectively. We describe clinically patients with the mutations T494G (Val165Gly), T134C (Leu045Pro), and C667A (Leu223Ile). We discuss also the previously reported mutations Asp202Asn and Asp202His. We have calculated the changes in hydrophobicity of short sequences surrounding some of these amino acids and compared the probable results of the changes in transmembrane structure of the proteolipid protein for the various mutations with the clinical data available on the patients. While the Val165Glu mutation, which is expected to produce disruption of a transmembrane loop of the protein, produces more severe disease than does Val165Gly, no particular correlation with hydrophobicity is found for the other mutations. As these are not in transmembrane domains, other factors such as intracellular transport or interaction between protein chains during myelin formation are probably at work.

Genotype–phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations

“…In addition, the missense and nonsense mutations affecting Q233 resulted in the same mild form (3). The two different aa substitutions reported in the conservative aa 223 (L223P and L223I), 21 caused a severe form of PMD. However, severe forms of PMD were also reported in two mutations affecting the non-conservative aa 45 (L45P and L45R), 21 suggesting that any change in the extracytoplasmic A-B loop is deleterious for oligodendrocytes.…”

“…This might be due to differences in hydrophobicity changes for the affected transmembrane helix C resulting from the substitution. 21 We classified the phenotype of the PLP-specific nonsense mutation in exon 3B (W144X) 22 as SPG, whereas the three patients were originally described as having a movement disorder (tremor, ataxia), apparently without spasticity, due to normal milestone achievement during the first year of life. In our series, SPG family 9 had a very similar PLP-specific abnormality: the five affected patients expressed a classical PMD3 or SPG phenotype.…”

Proton MR Spectroscopic Imaging in Pelizaeus-Merzbacher Disease

“…Singlestrand conformation polymorphism (SSCP) analysis of the PLP1 gene was performed as described previously by researchers in the Department of Molecular Genetics, Indiana University, Indianapolis, Indiana (18). Control subjects were the healthy siblings of patients (with other non-PMD diseases).…”

“…Genetic studies of the PLP1 gene revealed a T494G transversion, which is responsible for replacement of valine 165 by glycine (18). MR images obtained at the age of 1 month were normal, but at 2 years 4 months of age, T2-weighted MR images showed diffuse, patchy, and symmetrically increased signal intensity within the white matter.…”

Pelizaeus-Merzbacher disease: Genetic and cellular pathogenesis

“…An extensive collection of missense mutations (those mutations that result in amino acid substitution) in the PLP/DM20 gene exist. Certain amino acid codons have a particularly rich array of changes that offer an opportunity to investigate the consequences of a specific protein alteration on myelination and the clinical manifestations of PMD/SPG2 [139,140]. Three codons were mutated in two missense versions (V166E, V166G; L224I, L224P; Q234X, Q234P), and one codon was subjected to five different missense mutations: the aspartate at position 202 was changed to an asparagine, histidine, valine, glycine or glutamate residue in different PMD patients.…”