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)

M. E. Hodes, Andrew W. Zimmerman, Antonina Aydanian, Sakkubai Naidu, Neil R. Miller, José L. Garcia Oller, Bruce Barker, Kirk A. Aleck, Thomas Hurley, Stephen Dlouhy

Research output: Contribution to journalArticle

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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 ore 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.

Original languageEnglish
Pages (from-to)132-139
Number of pages8
JournalAmerican Journal of Medical Genetics
Volume82
Issue number2
DOIs
StatePublished - Jan 15 1999

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Pelizaeus-Merzbacher Disease
Proteolipids
Paraplegia
Codon
Genotype
Phenotype
Mutation
Proteins
Hydrophobic and Hydrophilic Interactions
Amino Acids
Proline
Leucine
Isoleucine
Asparagine
Oligodendroglia
Amino Acid Substitution
Myelin Sheath
Histidine
Glycine
Glutamic Acid

Keywords

  • Hydropathy plots
  • Mutations
  • Pelizaeus-Merzbacher disease
  • Proteolipid protein gene
  • X-linked spastic paraplegia

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

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). / Hodes, M. E.; Zimmerman, Andrew W.; Aydanian, Antonina; Naidu, Sakkubai; Miller, Neil R.; Garcia Oller, José L.; Barker, Bruce; Aleck, Kirk A.; Hurley, Thomas; Dlouhy, Stephen.

In: American Journal of Medical Genetics, Vol. 82, No. 2, 15.01.1999, p. 132-139.

Research output: Contribution to journalArticle

Hodes, M. E. ; Zimmerman, Andrew W. ; Aydanian, Antonina ; Naidu, Sakkubai ; Miller, Neil R. ; Garcia Oller, José L. ; Barker, Bruce ; Aleck, Kirk A. ; Hurley, Thomas ; Dlouhy, Stephen. / 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). In: American Journal of Medical Genetics. 1999 ; Vol. 82, No. 2. pp. 132-139.
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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 ore 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.",
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AU - Hodes, M. E.

AU - Zimmerman, Andrew W.

AU - Aydanian, Antonina

AU - Naidu, Sakkubai

AU - Miller, Neil R.

AU - Garcia Oller, José L.

AU - Barker, Bruce

AU - Aleck, Kirk A.

AU - Hurley, Thomas

AU - Dlouhy, Stephen

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