Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pelizaeus-Merzbacher disease (PMD) has been recognized as a clinical entity for more than a century. It has gradually become apparent that the disorder is a dysmyelination, in distinction to demyelinating conditions such as adrenoleukodystrophy. The failure to deposit myelin is due to decreased production of its chief protein, proteolipid protein (PLP). In about 30% of patients with the diagnosis of PMD there is a mutation in the coding portion of the proteolipid protein gene, PLP. This gene is located at Xq22 so the disease in these families shows an X-linked pattern of inheritance. The expression of the mutant gene is generally recessive, but some mutations are expressed frequently in females. At least some patients with PMD that do not show mutations in the coding region of PLP demonstrate linkage between the disease and PLP. As additional mutations in PLP are discovered, it is becoming apparent that the nosology of PLP-associated disease is changing. PMD now comprises a spectrum of disorders with similar but not necessarily identical clinical pictures. Some of these disorders may be certain forms of X-linked paraplegia, SPG2. Finally, some diseases that look like PMD may not be X-linked.
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PMID:Genetics of Pelizaeus-Merzbacher disease. 753 Jun 33

Proteolipid protein (PLP) is the major myelin protein of the CNS and is believed to have a structural role in maintaining the intraperiod line of compact myelin. An isoform, DM-20, produced by alternative splicing of exon 3B is expressed earlier than PLP in the CNS and may be involved in glial cell development. DM-20 is also present in myelin-forming and non-myelin-forming Schwann cells, olfactory nerve ensheathing cells, some glial cell lines and cardiac myocytes. Molecular studies suggest the existence of a PLP gene family with sequence similarities between molecules of different species. Such studies also lend credence to the suggestion that PLP and/or DM-20 may function as a membrane pore. Mutations in the PLP gene occur in several animal species and cause severe pleiotropic effects on myelination. In man this presents as Pelizaeus-Merzbacher disease (PMD). The phenotype of such mutants is characterized by dysmyelination with myelin of abnormal periodicity, paucity of mature oligodendrocytes and astrocytosis. Duplication of the PLP gene in transgenic animals or in one form of PMD also results in dysmyelination. X-linked spastic paraplegia (SPG2) is allelic to PMD and is associated with PLP mutations in which the levels of the DM-20 isoform are probably relatively normal. The effects of PLP gene dosage on CNS myelination can be compared in many ways to the variety of phenotypes in the PNS in hereditary neuropathies of the Charcot-Marie-Tooth type in which the peripheral myelin-22 gene is mutated.
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PMID:The proteolipid protein gene. 754 1

We report a dinucleotide polymorphism in the first intron of the proteolipid protein (PLP) gene with a heterozygosity frequency of 0.69 useful for molecular analysis of families with X-linked neurologic disorders characterized by dysmyelination of the central nervous system, Pelizaeus-Merzbacher Disease (PMD) and X-linked Spastic Paraplegia (SPG2).
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PMID:Dinucleotide repeat polymorphism in the proteolipoprotein (PLP) gene. 763 79

Three forms of X-linked spastic paraplegia (SPG) have been defined. One locus (SPG 1) maps to Xq28 while two clinically distinct forms map to Xq22 (SPG2). A rare X-linked dysmyelinating disorder of the central nervous system, Pelizaeus-Merzbacher disease (PMD), has also been mapped to Xq21-q22, and is caused by mutations in the proteolipid protein gene (PLP) which encodes two myelin proteins, PLP and DM20. While narrowing the genetic interval containing SPG2 in a large pedigree, we found that PLP was the closest marker to the disease locus, implicating PLP as a possible candidate gene. We have found that a point mutation (His139Tyr) in exon 3B of an affected male produces a mutant PLP but a normal DM20, and segregates with the disease (Zmax = 6.63, theta = 0.00). It appears, therefore, that SPG2 and PMD are allelic disorders.
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PMID:X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus. 801 87

X-linked hereditary spastic paraplegias (HSP) present with two distinct phenotypes, pure and complicated. The pure form is characterized by spasticity and gait difficulties but lacks the additional features (nystagmus, dysarthria, mental retardation) present in the complicated form. The complicated form is heterogeneous, caused by mutations of the L1CAM gene at Xq28 (SPG1) or the PLP gene at Xq22 (SPG2) that is allelic to Pelizaeus-Merzbacher disease (PMD). Since in one kindred (K313) the pure form of HSP was also mapped to Xq22, this raises the issue as to whether a pure form of HSP exists that is allelic to X-linked complicated HSP (SPG2) and PMD. To answer this question, we carried out linkage analysis in a new pedigree with pure HSP (K101) and refined linkage in pedigree K313. The PLP gene was also screened for mutation by direct sequencing and reverse-transcriptase polymerase chain reaction (RT-PCR). In both families, the disease locus mapped to Xq22 with Lod scores at zero recombination of 5.3 for COL4A5 2B6 in K313 and 2.4 for DXS101 in K101. A T to C transition in exon 5 of the PLP gene was identified from affected individuals of K313. This transition causes a Ser to Pro mutation in the major extracellular loop of PLP/DM20. This finding demonstrates that a form of X-linked pure spastic paraplegia, X-linked complicated HSP (SPG2) and PMD are allelic disorders. There was no evidence of mutations in either coding sequences or the intron/exon junctions of PLP in pedigree K101, suggesting that the disease-producing mutation may be in the noncoding portions of PLP or in a nearby gene.
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PMID:Refined genetic mapping and proteolipid protein mutation analysis in X-linked pure hereditary spastic paraplegia. 878 Jan 1

Familial spastic paraplegia (FSP or SPG) is a genetically heterogeneous group of upper motor neuron syndromes. To date, two distinct loci for X-linked recessive type (SPG1 and SPG2), three loci for autosomal dominant type (FSP1, FSP2 and FSP3), and one locus for autosomal recessive type have been reported. SPG1 and SPG2 have been mapped to Xq28 and Xq21-q22, respectively. SPG1 shows a mutation in the gene for neural cell adhesion molecule L1 (LICAM), which is an axonal glycoprotein involved in neuronal migration and differentiation. Different mutations of the same L1 gene also cause. MASA (mental retardation, aphasia, spastic paraplegia, adducted thumbs) syndrome and X-linked hydrocephalus. SPG2 shows mutations in one of the major myelin proteins, the proteolipid protein (PLP) gene, and is allelic to Pelizaeus-Merzbacher disease. Thus, mutations in two functionally distinct genes manifest the phenotype of X-linked spastic paraparesis. Three dominantly inherited spastic paraplegia genes have been genetically mapped to regions of chromosomes, yet no specific genes or mutations have been identified. FSP1 is mapped to a region of 7 cM on chromosome 14q12-q23 (approximately 20% of dominant FSP families) and FSP2 to 4 cM on chromosome 2p21-p24 (approximately 70% of dominant FSP families). Anticipation (increasing clinical severity in successive generations) has been observed in both FSP1 and FSP2 families. Another autosomal dominant FSP (FSP3) has been mapped in the centromeric region of chromosome 15q (< 10% of dominant FSP families). An autosomal recessive FSP has been mapped to chromosome 8q. The definite genetic heterogeneity in FSP indicates that a multitude of genes/proteins can cause spastic paraplegia. Clinical features of each of the loci which may permit differential diagnosis are discussed. We also present pedigrees of two new FSP families.
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PMID:Molecular genetics of familial spastic paraplegia: a multitude of responsible genes. 878 67

We have investigated a family with severe X-linked spastic paraplegia and assigned the disease locus to Xq11.2-q23 by linkage and haplotype analysis. This region harbors the gene coding for proteolipid protein, which is mutated in one of the two established forms of X-linked spastic paraplegia, i.e., SPG2. We have performed extensive mutation analysis of this gene. Our failure to detect a mutation in this family suggests a third locus in X-linked recessive spastic paraplegia.
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PMID:Evidence of a third locus in X-linked recessive spastic paraplegia. 925 66

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.
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PMID: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). 993 76

X-linked hereditary spastic paraplegias (HSPs) present with two distinct phenotypes: pure and complicated. The pure form is characterized by slowly progressive weakness and spasticity of the lower limbs, whereas the complicated forms have additional features (optic neuropathy, retinopathy, extrapyramidal disturbance, dementia, epilepsy, ataxia, ichthyosis, mental retardation, and deafness). Three X-linked loci have been identified for the complicated HSP, while mutations in the proteolipid gene (PLP) (locus SPG2) were implicated in both pure and complicated forms. The absence of identified mutations in the PLP gene in families with both complicated and pure HSP, linked to the SPG2 locus, suggests the existence of another gene in close proximity. We had previously reported a large pedigree with an X-linked form of pure HSP affecting 24 males [Zatz et al., 1976: J Med Genet 13:217-222]. Here, we present the results of linkage analysis in 19 members of this Brazilian family with markers in or near the PLP locus. Positive LOD scores were obtained with markers at the PLP locus (Zmax = 2.41 at Theta = 0); however, no mutation was found in the coding region of PLP, the intron-exon boundaries, or part of the promoter region. The possibility of a duplication of the PLP gene was also excluded. These results suggest either that there is another X-linked gene in close proximity to the PLP gene or that a novel mutation in the noncoding regions of the PLP gene may cause the disease in this family.
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PMID:Further evidence for a fourth gene causing X-linked pure spastic paraplegia. 1221 Mar 42

The proteolipid protein 1 (PLP1) gene encodes the two major proteins of the central nervous system (CNS) myelin: PLP and DM20. PLP1 gene mutations are associated with a large spectrum of X-linked dysmyelinating disorders ranging from hypomyelinating leukodystrophy, Pelizaeus-Merzbacher disease (PMD), to spastic paraplegia (SPG2) according to the nature of the mutation. Genetic heterogeneity exists and mutations in the gap-junction alpha 12 (GJA12) gene have been related to PMD. About 20% of patients with the PMD phenotype remain without mutation in these two genes and are classified as affected by Pelizaeus-Merzbacher-like disease (PMLD). To study PLP1 splicing abnormalities, we analyzed PLP/DM20 transcripts from nerves and/or skin cultured fibroblasts of 14 PMD/SPG2 patients carrying different PLP1 mutations and 20 PMLD patients. We found that various types of PLP1 mutations result in missplicing, including one considered as a missense in exon 2 and a nucleotide substitution in intron 3 outside the classical donor and acceptor splicing sites. Moreover, we demonstrated for two patients that the fibroblast transcript pattern was in accordance with the one observed in the corresponding CNS/peripheral nervous system (PNS) tissues. Finally, we observed no abnormal splicing in fibroblasts of 20 PMLD patients tested; suggesting that PLP1 gene splicing abnormalities, potentially caused by undetected intronic mutations, are either not involved or are very rarely implicated in the PMLD phenotype. These results confirm that fibroblasts are reliable, accessible cells useful in detecting PLP1 transcript abnormalities, better characterizing the functional consequences of PLP1 mutations for genotype-phenotype correlation, characterizing new PLP1 splicing regulatory elements, and identifying PLP1 mutations undetected by conventional PLP1 screening.
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PMID:PLP1 splicing abnormalities identified in Pelizaeus-Merzbacher disease and SPG2 fibroblasts are associated with different types of mutations. 1847 Sep 32


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