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

The X-linked mutation rumpshaker (rsh), which is probably an allele of jimpy (jp), causes hypomyelination in the CNS of mice. This study examines the developmental expression of the morphology, glial cells, and immunostaining of myelin proteins in the optic nerve and spinal cord. The optic nerve contains varying numbers of amyelinated and myelinated fibres. The majority of such sheaths are of normal thickness whereas in the spinal cord most axons are associated with a disproportionately thin sheath which changes little in thickness during development. In the optic nerve glial cell numbers are elevated in mutants during early and peak myelination but then fall slightly below normal in adults. In contrast, the number of glial cells is consistently elevated after 16 days of age in the spinal cord. The majority of the alterations to total glial cells are due to corresponding changes in the oligodendrocyte population. Immunostaining intensity is somewhat reduced for myelin basic protein (MBP) and the C-terminal common to proteolipid protein (PLP) and DM-20 and profoundly decreased for the PLP-specific peptide. Glial fibrillary acidic protein (GFAP) is increased in rsh. It is probable that some of the variation in myelination between optic nerve and cord in rsh is related to the difference in axon diameter in the two locations, as there are adequate numbers of oligodendrocytes at the time of myelination. However, the effect of the mutation on cell development in the brain and the spinal cord may be different. The immunostaining indicates a marked deficiency in PLP in myelin but suggests that DM-20 levels may be relatively normal. rsh shows several major differences from jp and other X-linked myelin mutants, particularly in relation to oligodendrocyte numbers, and will be useful to elucidate the role of the PLP gene in influencing oligodendrocyte differentiation and survival.
 ...
PMID:Rumpshaker: an X-linked mutation causing hypomyelination: developmental differences in myelination and glial cells between the optic nerve and spinal cord. 137 90

A family with an apparent history of X-linked Pelizaeus-Merzbacher disease presented for genetic counseling, requesting carrier detection and prenatal diagnosis. RFLP analysis using the proteolipid protein (PLP) gene probe was uninformative in this family. A prenatal diagnosis on a chorionic villus sample (CVS) was carried out using single-strand conformation polymorphism (SSCP) analysis of a variant in exon 4 of the PLP gene. The fetus was predicted to be unaffected. Sequencing of the exon from the CVS, the predicted-carrier mother, and the obligate-carrier grandmother revealed an A-to-C change at nucleotide 541 in the two women but not in the fetus. As this change results in a Thr-to-Pro change at amino acid 181 in a region of the gene predicted to be part of a transmembrane segment, it was concluded that this was the mutation causing the disease in this family. In addition, in a second family, an exon 5 variant band pattern on SSCP analysis was shown by sequencing to be due to a T-to-C change at nucleotide 668. This results in a Leu-to-Pro change in a carrier mother and in her two affected sons. These results provide further examples of mutations in PLP that cause Pelizaeus-Merzbacher disease and illustrate the value of SSCP in genetic analysis.
 ...
PMID:Pelizaeus-Merzbacher disease: detection of mutations Thr181----Pro and Leu223----Pro in the proteolipid protein gene, and prenatal diagnosis. 138 24

Myelin deficiency (md) in female rats due to a mutation in the X-linked proteolipid protein (PLP) gene is caused by X-chromosome monosomy. Cytogenetic analysis revealed a single X karyotype [41,X(md/0)]. An immunocytochemical, electron microscopic, and biochemical study was performed on male and female md rats. The central nervous system (CNS) of the female md rat [41,X(md/0)] revealed the same total lack of PLP as the CNS of the affected male littermate [42,XY(md/Y)]. Immunocytochemistry for myelin basic protein (MBP), myelin-associated glycoprotein (MAG), and 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNP) revealed "islands" of myelin sheath-like reaction product in both. Electron microscopy showed great paucity of compact myelin sheaths in 41,X(md/0) and 42,XY(md/Y). Reduced levels of MPB, MAG, and CNP were confirmed for both sexes but MAG and CNP were substantially higher in 41,X(md/0). Sexual differentiation of the brain may account for the observed differences since normal female reproductive organs are present in the md female rat.
 ...
PMID:Myelin deficiency in female rats due to a mutation in the PLP gene. 157 38

We report carrier identification and a prenatal diagnosis using DNA polymorphisms in 2 families with X-linked Pelizaeus-Merzbacher disease (PMD). In both families, the proteolipid protein (PLP) gene in the single affected male could be traced back to his unaffected maternal grandfather. Therefore, each family contains a new mutation. In the case of the prenatal diagnosis, the fetus was shown by cytogenetic analysis to be a female, who we predict will be a noncarrier of PMD based on her genotype with the PLP intragenic polymorphism.
 ...
PMID:Carrier detection and prenatal diagnosis of Pelizaeus-Merzbacher disease using a combination of anonymous DNA polymorphisms and the proteolipid protein (PLP) gene cDNA. 167 65

The capacity for synthesizing and maintaining a compact myelin sheath is destroyed in a number of inborn errors of myelin metabolism. One class of hypomyelinating mutations, which displays an X-linked pattern of inheritance, is distinguished by marked disturbances in oligodendrocyte differentiation. We have defined the molecular defect in one such mutant that lacks mature oligodendrocytes, the X-linked jimpy myelin synthesis deficient (jpmsd) trait in mice. The structure of the gene encoding the most abundant myelin protein, proteolipid protein (PLP), was determined by mapping and partially sequencing genomic clones from jpmsd and wild-type mice. Jpmsd mice have a single base change in PLP, a C----T transition in exon 6 that would substitute a valine for alanine in both PLP and its alternatively spliced isoform, DM20. The mutation was confirmed by polymerase chain reaction-amplifying exon 6 from genomic DNA and then either sequencing the amplified DNA or directly probing exon 6 with oligonucleotides designed to detect a single base mismatch. The conservative amino acid replacement in PLP/DM20 of jpmsd mice results in a pleiotropic phenotype similar to that observed for the allelic mutation jimpy, in which a splicing defect has radically altered the PLP/DM20 protein. The accelerated turnover of oligodendrocytes in both mouse mutants suggests a function for PLP/DM20 in oligodendrocyte differentiation distinct from the role of these proteolipid proteins as structural components of the myelin sheath.
 ...
PMID:Conservative amino acid substitution in the myelin proteolipid protein of jimpymsd mice. 168 31

Several genetic disorders that occur in animals and in humans result in an inability to synthesize normal myelin. Some of these disorders are inherited in an X-linked manner. The localization of the myelin proteolipid protein (PLP) gene to the X chromosome has directed the study of X-linked myelination disorders toward PLP. The myelin-deficient rat is one such X-linked dysmyelinating mutant. From a cDNA library constructed from myelin-deficient rat brain mRNA, we have isolated and sequenced cDNAs corresponding to PLP and its alternatively spliced isoform, DM-20. An A to C transition was detected in these cDNAs, which results in a threonine to proline change at amino acid 74 in both PLP and DM-20. No other substitutions were seen in the cDNA sequences. Polymerase chain reaction amplification and sequencing of the corresponding genomic regions were used to confirm the single base change. This substitution occurs in a highly hydrophobic portion of the protein that is thought to be an alpha-helical transmembrane segment. The presence of a helix-breaking amino acid such as proline in this segment is likely to influence the ability of the protein to interact with the membrane.
 ...
PMID:The myelin-deficient rat has a single base substitution in the third exon of the myelin proteolipid protein gene. 168 77

The myelin-deficient (md) rat is one of several X-linked animal mutants that have severe dysmyelination in the central nervous system. It appears in all to be the result of mutations in the myelin proteolipid protein gene which is located on the long arm of the X-chromosome. To identify the md rat mutation, we isolated and sequenced cDNAs corresponding to PLP and DM-20 mRNAs from the brain of hemizygous affected males. The only consistent sequence difference between these and normal rat sequences was the substitution of a C for an A at the first position of codon 74, resulting in a threonine to proline amino acid change. The presence of this helix-breaking amino acid in the second hydrophobic alpha-helical segment of the protein might be expected to influence its ability to interact with the membrane. PCR amplification and sequencing of the corresponding genomic regions were used to confirm the presence of the single base change in the hemizygote and both normal and mutant versions in the heterozygotes. It is interesting that this change, like those detected in other X-linked myelin disorders, involves an amino acid replacement within a hydrophobic alpha-helical segment of the PLP protein. Disruption of these structures apparently has severe consequences for the ability of PLP to contribute normally to myelination.
 ...
PMID:Single base substitution in codon 74 of the MD rat myelin proteolipid protein gene. 170 93

Immunocytochemistry and thymidine autoradiography were combined to determine the time elapsed between cell division and the expression of proteolipid protein (PLP) in individual oligodendrocytes in normal mouse brain. In jimpy (jp) brains, autoradiography was used to determine the time elapsed between cell division in an individual oligodendrocyte and evidence of cell death. Oligodendrocytes in normal mouse brain do not express PLP until 72 h after a single injection of [3H]-thymidine. In contrast, oligodendrocytes in jp brains begin to die within 9-11 h after an injection of thymidine. The jp mouse is one of several X-linked, hypomyelinated mutants in which a defect has been demonstrated in the gene coding for PLP. It has been presumed that the lack of this protein in the myelin sheath is responsible for the jp phenotype. However, the present study shows that individual jp oligodendrocytes begin to die long before they would normally have synthesized detectable levels of PLP. Therefore, it seems unlikely that the death of jp oligodendrocytes is due to the absence of PLP in myelin sheaths. Oligodendrocyte death and other early jp abnormalities may be due to the presence of abnormal PLP message which may interfere with glial differentiation. Alternatively, the PLP message may code for another protein which is important for normal development of neuroglia.
 ...
PMID:Death of individual oligodendrocytes in jimpy brain precedes expression of proteolipid protein. 170 11

A group of inherited neurological disorders are the X-chromosome linked dysmyelinoses, in which myelin membranes of the CNS are missing or perturbed due to a strongly reduced number of differentiated oligodendrocytes. In animal dysmyelinoses (jimpy mouse, msd-mouse, md rat, shaking pup) mutations of the main integral myelin membrane protein, proteolipid protein, have been identified. Pelizaeus-Merzbacher disease (PMD) or sudanophilic leucodystrophy is an X-linked dysmyelinosis in humans. We report here on the molecular basis of the defect of affected males of a PMD kindred. Rearrangements of the PLP gene were excluded by Southern blot hybridisation analysis and PCR amplification of overlapping domains of the PLP gene. Sequence analysis revealed one single C----T transition in exon IV, which leads to a threonine----isoleucine substitution within a hydrophobic intramembrane domain. The impact of this amino-acid exchange on the structure of PLP in the affected cis membrane domain is discussed. A space filling model of this domain suggests a tight packing of the alpha-helices of the loop which is perturbed by the amino-acid substitution in this PMD exon IV mutant. The C----T transition in exon IV abolishes a Hph I restriction site. This mutation at the recognition site for Hph I (RFLP) and allele-specific primers have been used for mutation screening the PMD kindred.
 ...
PMID:A point mutation at the X-chromosomal proteolipid protein locus in Pelizaeus-Merzbacher disease leads to disruption of myelinogenesis. 170 72

The differentiation of the oligodendrocyte from its bipotential progenitor culminates in the production of the myelin-specific proteins and the elaboration of membrane processes that ensheath the axon. Mutations in proteolipid protein (PLP) and its alternatively spliced isoform DM-20, the major protein constituents of central nervous system myelin, are characterized by a significant reduction in the number of mature oligodendrocytes, resulting in severe hypomyelination, tremor and early death. The canine shaking pup carries such a mutation, a single base change that substitutes a proline for a histidine near the first transmembrane region of PLP and DM-20. This mutation hinders oligodendrocyte differentiation, as evidence by a splicing pattern at the PLP locus characteristic of immature oligodendrocytes. The spliced transcript expressed earliest in development, DM-20, continues to be overexpressed in shaking pup oligodendrocytes. The disruption of the normal maturation schedule in these X-linked dysmyelinating disorders suggests that PLP or DM-20 plays a fundamental role in oligodendrocyte development. We propose that, while the more abundant PLP is the primary structural component of myelin, DM-20 may be critical to oligodendrocyte maturation.
 ...
PMID:A point mutation in the proteolipid protein gene of the 'shaking pup' interrupts oligodendrocyte development. 172 45


1 2 3 4 5 6 7 8 9 Next >>