Pelizaeus–Merzbacher disease
•
1 like•2,058 views
The document discusses Pelizaeus-Merzbacher Disease (PMD), a rare degenerative neurological disorder caused by mutations in the proteolipid protein 1 (PLP1) gene. PMD affects the growth of the myelin sheath and causes deterioration of motor and intellectual abilities. There are different types of PMD classified by severity, from the most severe connatal PMD to pure spastic paraplegia 2. Animal studies showed that PLP deficiency relates to myelin deficiencies in mutants like the jimpy mouse. The disease mechanism involves PLP1's role in myelin structure and how various mutations affect its function.
Recommended
Recommended
More Related Content
What's hot
What's hot (20)
Similar to Pelizaeus–Merzbacher disease
Similar to Pelizaeus–Merzbacher disease (20)
More from Shashank Chintalagiri
More from Shashank Chintalagiri (13)
Recently uploaded
Recently uploaded (20)
Pelizaeus–Merzbacher disease
- 1. Pelizaeus- Merzbacher Disease Chintalagiri Shashank, chin- tal@iitk.ac.in Pelizaeus-Merzbacher Disease Outline BSE638 - Structural Basis of Protein Function Introduction Pelizaeus- Merzbacher Disease Types of PMD Chintalagiri Shashank, chintal@iitk.ac.in Disease Mechanism Pathogenesis Animal Mutants Molecular April 29, 2010 Pathogenesis Genotype - Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 2. Pelizaeus- Merzbacher Disease 1 Introduction Chintalagiri Shashank, Pelizaeus-Merzbacher Disease chin- tal@iitk.ac.in Types of PMD Outline 2 Disease Mechanism Introduction Pelizaeus- Merzbacher Disease Types of PMD 3 Pathogenesis Disease Animal Mutants Mechanism Molecular Pathogenesis Pathogenesis Animal Mutants Genotype - Phenotype correlation Molecular Pathogenesis Genotype - Phenotype correlation 4 References References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 3. Pelizaeus-Merzbacher Disease[1] Pelizaeus- Merzbacher Rare, progressive, degenerative central nervous system Disease disorder Chintalagiri Shashank, chin- Coordination, motor abilities, and intellectual function tal@iitk.ac.in deteriorate Outline One of a group of gene-linked disorders known as the Introduction leukodystrophies, affects growth of the myelin sheath. Pelizaeus- Merzbacher Disease The disease is caused by a mutation in the gene encoding Types of PMD a myelin protein called proteolipid protein-1 (PLP1). Disease Mechanism PMD is inherited as an X-linked recessive trait; the Pathogenesis affected individuals are male and the mothers are carriers Animal Mutants Molecular Pathogenesis of the PLP1 mutation. Genotype - Phenotype correlation Severity and onset of the disease ranges widely, depending References on the type of PLP1 mutation. One of a spectrum of diseases associated with PLP1. Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 4. Types of PMD[1] Pelizaeus- Merzbacher There are 4 general classifications within this spectrum of Disease diseases. In order of severity, they are: Chintalagiri Shashank, Connatal PMD, which is the most severe type and involves chin- tal@iitk.ac.in delayed mental and physical development and severe neurological symptoms Outline Classic PMD, in which the early symptoms include muscle Introduction Pelizaeus- Merzbacher weakness, involuntary movements of the eyes Disease Types of PMD (nystagmus), and delays in motor development within the Disease first year of life Mechanism Complicated SPG2, which features motor development Pathogenesis Animal Mutants issues and brain involvement Molecular Pathogenesis Genotype - Pure SPG2, which includes cases of PMD that do not Phenotype correlation have neurologic complications. References Noticeable changes in the extent of myelination can be detected by MRI analyses of the brain. Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 5. Pelizaeus- Merzbacher Disease Chintalagiri Shashank, chin- tal@iitk.ac.in Modern morphological, biochemical, and molecular techniques Outline have made this distinction obsolete, and PMD must now be Introduction Pelizaeus- considered a leukodystrophy with variable clinical and Merzbacher Disease Types of PMD neuropathological phenotypes, although all cases are due to Disease mutations of the proteolipid protein (PLP) gene. Mechanism Pathogenesis Animal Mutants Molecular Pathogenesis Genotype - Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 6. Disease Mechanism Pelizaeus- Merzbacher Disease Chintalagiri Shashank, Proposed roles for PLP1 include mediating interlamellar chin- tal@iitk.ac.in adhesion in compact myelin, mediating ion flux, and acting as an oligodendrocyte precursor mitogen. Outline Introduction Pelizaeus- Merzbacher PLP is a major structural component of CNS myelin, whereas Disease Types of PMD DM20 which is produced earlier in CNS development may be Disease involved in oligodendrocyte differentiation and survival. Mechanism Pathogenesis Animal Mutants Complete deficiency of PLP1 does not prevent myelination, but Molecular Pathogenesis Genotype - it does result in late-onset axonal degeneration. Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 7. Disease Mechanism Pelizaeus- Merzbacher Disease Chintalagiri Shashank, In addition to null mutations, mutations that disrupt the chin- tal@iitk.ac.in PLP1-specific region, a 35-amino-acid region that is spliced out during formation of the DM20 isoform, cause both peripheral Outline Introduction neuropathy and central axonal degeneration. Pelizaeus- Merzbacher Disease Types of PMD Single amino-acid changes in highly conserved regions of the Disease DM20 protein caused the most severe forms of PMD. Mechanism Substitutions of less conserved amino acids, truncations, Pathogenesis Animal Mutants absence of the protein and PLP-specic mutations cause the Molecular Pathogenesis Genotype - milder forms of PMD and SPG. Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 8. Disease Mechanism Pelizaeus- Merzbacher Disease Chintalagiri Shashank, chin- tal@iitk.ac.in Gow and Lazzarini have suggested a cellular mechanism for Outline disease severity in PMD. They reported that classical PMD Introduction Pelizaeus- correlates with misfolding and accumulation of PLP1 in the Merzbacher Disease endoplasmic reticulum (ER) and transport of DM20 to the cell Types of PMD Disease surface, while connatal PMD correlates with misfolding and Mechanism accumulation of both PLP1 and DM20 in the ER. Pathogenesis Animal Mutants Molecular Pathogenesis Genotype - Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 9. Pathogenesis Pelizaeus- Merzbacher Disease Chintalagiri Shashank, chin- tal@iitk.ac.in Gencic et.al.[5] report that the underlying disturbance in myelination of Pelizaeus-Merzbacher patients was Outline attributed to a failure to form myelin (dys-myelination) Introduction Pelizaeus- rather than to a breakdown of preexisting myelin Merzbacher Disease (demyelination) by a pathogenic analysis by Zeman et.al. Types of PMD Disease in 1964. Mechanism Zeman et.al. also predicted that the defect would involve Pathogenesis Animal Mutants a myelin protein or proteolipid Molecular Pathogenesis Genotype - Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 10. Animal Mutants Pelizaeus- Merzbacher Disease Chintalagiri Shashank, PLP deficiency relates to a X-linked CNS myelin deficiency in chin- tal@iitk.ac.in several animal mutants jimpy mouse (jp) is the oldest and best known Outline Introduction the myelin-deficient rat (md) Pelizaeus- Merzbacher Disease the shaking pup (sh) Types of PMD Disease the rumpshaker mouse (rsh) Mechanism the rabbit with paralytic tremor (pt) Pathogenesis Animal Mutants Molecular The deficiency of PLP protein was commensurate with low Pathogenesis Genotype - levels of the matching messenger ribonucleic acid (mRNA). Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 11. Implication of PLP Pelizaeus- Merzbacher Disease Two observations focused attention on the major structural Chintalagiri Shashank, protein of myelin, proteolipid protein (PLP), as a candidate for chin- tal@iitk.ac.in mutation in Pelizaeus-Merzbacher disease. Outline Assignment of the PLP gene to the human X chromosome Introduction at position Xq22, which supported the X-linked Pelizaeus- Merzbacher inheritance of the disease. Disease Types of PMD Discovery that the dysmyelinating mouse mutant jimpy, Disease Mechanism which appears pathologically and genetically similar to Pathogenesis Pelizaeus-Merzbacher disease, has a mutation in the PLP Animal Mutants Molecular gene that results in aberrantly spliced PLP transcripts Pathogenesis Genotype - (Morello et al. 1986; Nave et al. 1986, 1987; Hudson et Phenotype correlation al. 1987; Macklin et al. 1987; Ikenaka et al. 1988). References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 12. Myelin[8] Pelizaeus- Merzbacher Disease Chintalagiri Shashank, chin- tal@iitk.ac.in Outline Introduction Pelizaeus- Merzbacher Disease Types of PMD Disease Mechanism Pathogenesis Animal Mutants Molecular Pathogenesis Genotype - Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 13. Structure of PLP Pelizaeus- Merzbacher Disease Chintalagiri Shashank, chin- tal@iitk.ac.in Outline Introduction Pelizaeus- Merzbacher Disease Types of PMD Disease Mechanism Pathogenesis Animal Mutants Molecular Pathogenesis Genotype - Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 14. Structure of PLP Pelizaeus- Merzbacher PLP is a tetraspan protein, with 4 TM α-helices spanning Disease the myelin membrane. Both N- and C-terminals are in the Chintalagiri Shashank, cytoplasmic side. chin- tal@iitk.ac.in Immunolabeling studies of PLP and several protein structure prediction algorithms were used to determine the Outline Introduction most likely residues making up the α-helices. Pelizaeus- Merzbacher The region of PLP that is deleted in DM20 (residues 116 Disease Types of PMD 150) is shown in yellow. Disease Cysteines involved in the formation of the two disulde Mechanism bonds in PLP (linking residues 183 227 and 200 219) are Pathogenesis Animal Mutants shown in blue. Molecular Pathogenesis Genotype - 6 cysteine residues are thought to be acylated (shown in Phenotype correlation red), with palmitic acid sidechains attached. Alternatively, References some of these cysteine residues could be involved in disulde linkages. Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 15. Structure of PLP Pelizaeus- Merzbacher Disease Chintalagiri Shashank, chin- Structural properties of proteins specic to the myelin sheath, tal@iitk.ac.in Amino Acids (2008)[12] Outline Some of the myelin proteins, belonging to the family Introduction Pelizaeus- of tetraspanins, are amongst the most hydrophobic Merzbacher Disease Types of PMD proteins known. One of these proteins is the Disease proteolipid protein. This group of proteins is most Mechanism poorly characterised structurally, and will not be Pathogenesis Animal Mutants discussed in this review. Molecular Pathogenesis Genotype - Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 16. Mutation of PLP Pelizaeus- Merzbacher Disease Chintalagiri Shashank, chin- tal@iitk.ac.in The mutation causing PMD seems to be different for different families. Outline Introduction PMD is always caused by a mutation of PLP. Pelizaeus- Merzbacher Disease A majority of the cases seem to be caused by duplications Types of PMD involving the entire gene (larger than 100 kb) Disease Mechanism In some families, PMD is caused by the mutation of a Pathogenesis Animal Mutants single amino acid. Molecular Pathogenesis Genotype - Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 17. Mutations[2] Pelizaeus- Merzbacher Disease Chintalagiri Shashank, chin- tal@iitk.ac.in Clinical observations and studies of PLP mutations in animals and cell cultures suggest that there at least 3 distinct genetic Outline mechanisms that cause PMD. [2] Introduction Pelizaeus- Merzbacher Disease In addition, spastic paraplegia 2 (SPG2) is allelic to PMD and Types of PMD Disease typically caused by missense mutations in the second Mechanism extracellular domain of PLP1 or in the PLP1-specific region Pathogenesis Animal Mutants that is spliced out during formation of the DM20 isoform. Molecular Pathogenesis Genotype - Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 18. Molecular mechanisms of PMD pathogenesis[3] Pelizaeus- Merzbacher Disease Chintalagiri Shashank, chin- tal@iitk.ac.in Outline Introduction Pelizaeus- Merzbacher Disease Types of PMD Disease Mechanism Pathogenesis Animal Mutants Molecular Pathogenesis Genotype - Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 19. Pelizaeus- Merzbacher Disease Chintalagiri Shashank, chin- The first of these mechanisms produces loss of PLP function, tal@iitk.ac.in in which PLP does not accumulate in the cell. To date, 4 Outline so-called null mutations that cause PMD have been identified, Introduction including a deletion of the entire PLP gene, all of which Pelizaeus- Merzbacher produce a similar, relatively mild clinical phenotype. Disease Types of PMD Disease Mechanism Noncoding mutations affecting splicing of PLP1 and deletions Pathogenesis have been described in patients with PMD with the lowest Animal Mutants Molecular frequency. Pathogenesis Genotype - Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 20. Pelizaeus- Merzbacher The second of these genetic mechanisms produces a Disease gain-of-toxic function. Experimental evidence supports this Chintalagiri Shashank, mechanism. Gain-of-function mutations, typically amino acid chin- tal@iitk.ac.in substitutions, prevent PLP from reaching the cell surface by disrupting normal PLP folding. The mutant protein then Outline accumulates in the endoplasmic reticulum, somehow triggering Introduction Pelizaeus- increased oligodendrocyte cell death by apoptosis, with Merzbacher Disease Types of PMD resultant dysmyelination. The clinical phenotype caused by a Disease gain-of-function mutation depends on the location of the Mechanism altered amino acid, as well as on the particular amino acid Pathogenesis Animal Mutants substituted. Molecular Pathogenesis Genotype - Phenotype correlation Over 100 point mutations in the PLP1 coding region have been References identified, and these account for approximately 15% to 20% of PMD cases. Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 21. Pelizaeus- Merzbacher Disease The third and most common genetic mechanism is duplication Chintalagiri of the region of the X chromosome that contains the PLP Shashank, chin- gene. Since overexpression of PLP and/or DM20 is sufficient to tal@iitk.ac.in cause both CNS dysmyelination and subsequent demyelination Outline in transgenic mice, the human duplication probably produces Introduction PMD for similar reasons. The molecular mechanisms Pelizaeus- Merzbacher Disease underlying the PLP duplication have not yet been elucidated. Types of PMD The breakpoints of the PLP duplication often vary between Disease Mechanism patients, and inclusion of flanking genes in addition to PLP Pathogenesis and/or disruption of a flanking gene may explain differences in Animal Mutants Molecular phenotypic severities among patients with PLP duplication. Pathogenesis Genotype - Phenotype correlation This mutation probably accounts for 50% to 70% of the cases References of PMD. Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 22. Pelizaeus- Merzbacher Disease Chintalagiri Shashank, chin- tal@iitk.ac.in Genotype - phenotype correlation in PLP disease Cailloux et al, 2000 Outline Introduction 52 PMD and 28 SPG families selected for sequencing of Pelizaeus- Merzbacher the seven coding regions and the exon/intron junctions of Disease Types of PMD the PLP gene Disease Mechanism Identied 33 abnormalities (29 in PMD patients, 4 in SPG Pathogenesis patients) Animal Mutants Molecular Pathogenesis Genotype - Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 23. Type and Position of Mutation Pelizaeus- Merzbacher Disease Twenty-three were missense mutations, three were Chintalagiri Shashank, deletion/insertions with frameshifts and seven were chin- tal@iitk.ac.in splice-site mutations. Outline Mutations were in Introduction 1 coding regions in 24 of 29 PMD patients (80%) Pelizaeus- Merzbacher 2 exons 2 (29%), 4 (29%) and 5 (21%) Disease Types of PMD 3 2 of the mutations in SPG patients were in the Disease PLP-specific coding region, exon 3B. Mechanism 4 No mutations were observed in exons 1 and 7 of PLP Pathogenesis Animal Mutants Of the 23 aa changes resulting from missense mutations Molecular Pathogenesis 1 48% affected the CD loop Genotype - Phenotype correlation 2 each of the other locations accounted for only 4 to 13% of References the mutations. Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 24. Correlation between severity and type of mutation Pelizaeus- Merzbacher Disease Chintalagiri Shashank, chin- tal@iitk.ac.in Missense mutations were observed in two thirds of cases Outline for the severe forms and in one third of cases for the Introduction Pelizaeus- Merzbacher milder forms . Disease Types of PMD All other types of abnormality were observed almost Disease Mechanism exclusively in the mildest forms (80%). Pathogenesis Animal Mutants Molecular Pathogenesis Genotype - Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 25. Correlation between disease severity and the position of exonic mutations Pelizaeus- Merzbacher Disease Of the 26 mutations in coding regions Chintalagiri Shashank, 1 15 were responsible for severe PMD forms (57%) chin- tal@iitk.ac.in 2 9 for mild PMD forms (35%) 3 2 for SPG form 4 (8%) Outline Introduction In terms of exons, Pelizaeus- Merzbacher 1 Mutations causing severe forms of PMD mapped Disease Types of PMD essentially to exons 2 (40%) and 4 (33%), more rarely to Disease exons 6 (15%), 5 (7%), and 3A (7%), and never to exons Mechanism 1, 3B and 7. Pathogenesis 2 Mutations causing mild forms of PMD mapped Animal Mutants Molecular predominantly to exon 5 (44%), more rarely to exons 4 Pathogenesis Genotype - Phenotype (22%), 6 (22%) and 2 (12%). correlation 3 SPG mutations mapped exclusively to exon 3B. References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 26. Schematic representation of PLP Pelizaeus- Merzbacher Disease Chintalagiri Shashank, chin- tal@iitk.ac.in Outline Introduction Pelizaeus- Merzbacher Disease Types of PMD Disease Mechanism Pathogenesis Animal Mutants Molecular Pathogenesis Genotype - Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 27. Severity of the disease Pelizaeus- Merzbacher Disease Chintalagiri Shashank, chin- tal@iitk.ac.in Outline Introduction Pelizaeus- Merzbacher Disease Types of PMD Disease Mechanism Pathogenesis Animal Mutants Molecular Pathogenesis Genotype - Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 28. Correlation between severity the type of AA substitution resulting from missense mutations Pelizaeus- Merzbacher Changes in the PLP-specific BC loop were responsible for Disease the SPG phenotype. Chintalagiri Shashank, chin- Ten of the 11 substitutions in the AB extracytoplasmic tal@iitk.ac.in loop and the 4 transmembrane segments of the Outline PLP/DM20 protein caused severe forms of PMD. Introduction Five of the 11 substitutions in the CD loop caused severe Pelizaeus- Merzbacher Disease PMD and 6 mild PMD. Types of PMD Disease 3 families had three different exon 4 mutations resulting in Mechanism the substitution of the same amino acid, at position 202 in Pathogenesis Animal Mutants the PLP/DM20 protein (D202N, D202G,D202E) and had Molecular Pathogenesis the most severe form of PMD. Genotype - Phenotype correlation 2 families had two different exon 5 mutations resulting in References substitution of the same amino acid, at position 215 (P215S, P215A). Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 29. Correlation between severity the type of AA substitution resulting from missense mutations Pelizaeus- Merzbacher Disease Chintalagiri Shashank, chin- Replacement of a highly conserved amino acid, whatever tal@iitk.ac.in the new amino acid, caused the most severe forms of Outline PMD, whereas substitutions of less conserved amino acids Introduction caused milder forms. Pelizaeus- Merzbacher Disease In 2 cases, a severe form of PMD was observed (Y174C Types of PMD and A247E), despite substitution of a poorly conserved Disease Mechanism amino acid. In two cases, a severe form of PMD was Pathogenesis observed (Y174C and A247E), despite substitution of a Animal Mutants Molecular Pathogenesis poorly conserved amino acid. Genotype - Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 30. List of point mutations Pelizaeus- Merzbacher Disease Chintalagiri Shashank, chin- tal@iitk.ac.in Outline Introduction Pelizaeus- Merzbacher Disease Types of PMD Disease Mechanism Pathogenesis Animal Mutants Molecular Pathogenesis Genotype - Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 31. Distribution of point mutations Pelizaeus- Merzbacher Disease Chintalagiri Shashank, chin- tal@iitk.ac.in Outline Introduction Pelizaeus- Merzbacher Disease Types of PMD Disease Mechanism Pathogenesis Animal Mutants Molecular Pathogenesis Genotype - Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 32. Myelin Composition[8](2009) Pelizaeus- Merzbacher Disease Chintalagiri Shashank, chin- tal@iitk.ac.in Outline Introduction Pelizaeus- Merzbacher Disease Types of PMD Disease Mechanism Pathogenesis Animal Mutants Molecular Pathogenesis Genotype - Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 33. References I Pelizaeus- Merzbacher NINDS; Pelizaeus-Merzbacher Disease Information Page Disease http://www.ninds.nih.gov/disorders/pelizaeus_merzbacher/pelizaeus_merzbacher.htm. Chintalagiri James Garbern et.al.; The Molecular Pathogenesis of Pelizaeus-Merzbacher Disease, Arch. Neurol., Shashank, chin- VOL 56, Oct 1999 tal@iitk.ac.in J. Y. Garbern; Pelizaeus-Merzbacher disease:Genetic and cellular pathogenesis; Cell. Mol. Life Sci. 64 (2007) 50 65 Outline Introduction Fabrice Cailloux et.al; Genotypephenotype correlation in inherited brain myelination defects due to Pelizaeus- proteolipid protein gene mutations; Eur. J. Hum. Genet. (2000) 8, 837845 Merzbacher Disease Types of PMD Simonida Gencic et.al.; Pelizaeus-Merzbacher Disease: An X-linked Neurologic Disorder of Myelin Metabolism with a Novel Mutation in the Gene Encoding Proteolipid Protein, Am. J. Hum. Genet. Disease 45:435-442, 1989 Mechanism Pathogenesis Judith M. Greer, Marjorie B. Lees; Myelin proteolipid proteinthe rst 50 years; Int. J. Biochem. & Cell Animal Mutants Biol. 34 211215; 2002 Molecular Pathogenesis Eun Sil Lee et.al.; A case of complicated spastic paraplegia 2 due to a point mutation in the Genotype - Phenotype proteolipid protein 1 gene; J. Neu. Sci. 224 (2004) 83 87 correlation References Olaf Jahn, Stefan Tenzer, Hauke B. Werner;Myelin Proteomics: Molecular Anatomy of an Insulating Sheath; Mol Neurobiol (2009) 40:5572 Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease
- 34. References II Pelizaeus- Merzbacher Disease Chintalagiri Shashank, chin- Marie-Noelle Bonnet-Dupeyron et.al.;PLP1 Splicing Abnormalities Identified in Pelizaeus-Merzbacher tal@iitk.ac.in Disease and SPG2 Fibroblasts Are Associated With Different Types of Mutations; Hum. Mut. 29(8), 1028 - 1036, 2008 Outline Ken Inoue;PLP1-related inherited dysmyelinating disorders:Pelizaeus-Merzbacher disease and spastic Introduction Pelizaeus- paraplegia type 2; Neurogenetics (2005) 6: 1 16 Merzbacher Disease Olaf Maier et.al.;Polarity Development in Oligodendrocytes: Sorting and Trafficking of Myelin Types of PMD Components; J Mol Neurosci (2008) 35:35 53 Disease Mechanism P. Kursula; Structural properties of proteins specic to the myelin sheath; Amino Acids (2008) 34: 175 Pathogenesis 185 Animal Mutants Molecular Pathogenesis Genotype - Phenotype correlation References Chintalagiri Shashank, chintal@iitk.ac.in Pelizaeus-Merzbacher Disease