G2Cdb::Human Disease report

Disease id
D00000189
Name
Spastic paraplegia (X-linked)
Nervous system disease
yes

Genes (2)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00001881 L1CAM
L1 cell adhesion molecule
Y (7920659) Deletion (D) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (7920659) Microinsertion (MI) Y
G00001806 PLP1
proteolipid protein 1
Y (9489796) Polymorphism (P) Y
G00001806 PLP1
proteolipid protein 1
Y (9934976) Polymorphism (P) Y

References

  • 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 ME, Zimmerman AW, Aydanian A, Naidu S, Miller NR, Garcia Oller JL, Barker B, Aleck KA, Hurley TD and Dlouhy SR

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202-5251, USA. mhodes@medgen.iupui.edu

    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.

    American journal of medical genetics 1999;82;2;132-9

  • X-linked spastic paraplegia due to a mutation (C506T; Ser169Phe) in exon 4 of the proteolipid protein gene (PLP).

    Hodes ME, Hadjisavvas A, Butler IJ, Aydanian A and Dlouhy SR

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202-5251, USA. mhodes@medgen.iupui.edu

    A transition C506T was found in exon 4 of the proteolipid protein gene of a boy with spastic paraplegia. This mutation resulted in the substitution of phenylalanine for serine 169, which is in the third transmembrane domain of the proteolipid protein molecule. The mutation apparently arose de novo, as it was absent from his mother.

    American journal of medical genetics 1998;75;5;516-7

  • X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene.

    Jouet M, Rosenthal A, Armstrong G, MacFarlane J, Stevenson R, Paterson J, Metzenberg A, Ionasescu V, Temple K and Kenwrick S

    Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK.

    X-linked hydrocephalus, spastic paraplegia type I and MASA syndrome are related disorders with loci in subchromosomal region Xq28. We have previously shown that X-linked hydrocephalus is caused by mutations in the gene for neural cell adhesion molecule L1 (L1CAM), an axonal glycoprotein involved in neuronal migration and differentiation. Here we report mutations of the L1 gene in MASA syndrome and SPG1, in addition to HSAS families. Two of the HSAS mutations would abolish cell surface expression of L1 and represent the first functional null mutations in this disorder. Our results indicate that these three syndromes from part of a clinical spectrum resulting from a heterogeneous group of mutations in the L1 gene.

    Nature genetics 1994;7;3;402-7

Literature (3)

Pubmed - other

  • 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 ME, Zimmerman AW, Aydanian A, Naidu S, Miller NR, Garcia Oller JL, Barker B, Aleck KA, Hurley TD and Dlouhy SR

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202-5251, USA. mhodes@medgen.iupui.edu

    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.

    American journal of medical genetics 1999;82;2;132-9

  • X-linked spastic paraplegia due to a mutation (C506T; Ser169Phe) in exon 4 of the proteolipid protein gene (PLP).

    Hodes ME, Hadjisavvas A, Butler IJ, Aydanian A and Dlouhy SR

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202-5251, USA. mhodes@medgen.iupui.edu

    A transition C506T was found in exon 4 of the proteolipid protein gene of a boy with spastic paraplegia. This mutation resulted in the substitution of phenylalanine for serine 169, which is in the third transmembrane domain of the proteolipid protein molecule. The mutation apparently arose de novo, as it was absent from his mother.

    American journal of medical genetics 1998;75;5;516-7

  • X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene.

    Jouet M, Rosenthal A, Armstrong G, MacFarlane J, Stevenson R, Paterson J, Metzenberg A, Ionasescu V, Temple K and Kenwrick S

    Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK.

    X-linked hydrocephalus, spastic paraplegia type I and MASA syndrome are related disorders with loci in subchromosomal region Xq28. We have previously shown that X-linked hydrocephalus is caused by mutations in the gene for neural cell adhesion molecule L1 (L1CAM), an axonal glycoprotein involved in neuronal migration and differentiation. Here we report mutations of the L1 gene in MASA syndrome and SPG1, in addition to HSAS families. Two of the HSAS mutations would abolish cell surface expression of L1 and represent the first functional null mutations in this disorder. Our results indicate that these three syndromes from part of a clinical spectrum resulting from a heterogeneous group of mutations in the L1 gene.

    Nature genetics 1994;7;3;402-7

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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