myelin-basic-protein and Chromosome-Deletion

We report here an infant with 18q deletion syndrome, and intractable apneic seizures. He had intrauterine growth retardation and dysmorphic features. Chromosomal analysis demonstrated mosaicism of 18q interstitial deletion (q12.3-q22.3). From the age of 3 months, apneic attacks occurred from once a week to over 10 times a day despite many oral antiepileptic agents, and were diagnosed as complex partial seizures. Ictal electroencephalogram and 18F-fluorodeoxyglucose-positron emission tomography at the age of 10 months identified the epileptic focus in the right parieto-temporal region. He also had severe psychomotor retardation. Head MRI examination revealed diffuse cerebral atrophy and severe white matter dysmyelination, which was caused by the deletion of myelin basic protein gene at the locus of 18q22.3. This locus may be responsible for the clinical manifestations of 18q deletion syndrome. Detailed description of the onset, seizure types, and prognosis of epilepsy associated with 18q deletion syndrome is rare. It was suggested that the locus of 18q21.3-q22.3 was responsible for autonomic seizures in 18q deletion syndrome.

Topics: Apnea; Brain Diseases; Chromosome Deletion; Chromosomes, Human, Pair 18; Demyelinating Diseases; Epilepsy, Complex Partial; Gene Deletion; Humans; Infant; Infant, Newborn; Male; Myelin Basic Protein; Syndrome

We studied 14 individuals with partial deletions of the long arm of chromosome 18, including terminal and interstitial de novo and inherited deletions. Study participants were examined clinically and by brain MRI. The size of the deletion was determined by segregation analysis using microsatellite markers. We observed that the phenotype was highly variable, even in two families with three 1st degree relatives. Among the 14 individuals, general intelligence varied from normal to severe mental retardation. The more common features of 18q-deletions (e.g., foot deformities, aural atresia, palatal abnormalities, dysmyelination, and nystagmus) were present in individuals lacking only the distal portion 18q22.3-qtel. Interstitial deletions exerted very heterogeneous effects on phenotype. In individuals with distal 18q22.3-q23 deletions, brain MRI was very distinctive with poor differentiation of gray and white matter on T2-weighted images.

Topics: Abnormalities, Multiple; Adolescent; Adult; Brain; Child; Child, Preschool; Chromosome Deletion; Chromosome Segregation; Chromosomes, Human, Pair 18; Female; Humans; Infant; Intellectual Disability; Magnetic Resonance Imaging; Male; Microsatellite Repeats; Myelin Basic Protein; Phenotype

To study brain MRI findings in patients with 18q- syndrome and to correlate these findings with the results of the molecular breakpoint analysis.. Brain MR images of 17 patients with 18q- syndrome were evaluated. Segregation analysis was performed with 15 microsatellite markers to determine the deletion breakpoints and whether the deletion included the myelin basic protein (MBP) gene.. One patient had an interstitial deletion of 18q which spared the MBP gene. He was the only one with normal brain MRI. All 16 patients with deletions including the MBP gene had abnormal white matter in MRI. The main finding was poor differentiation of gray and white matter on T2-weighted images due to increased white matter signal intensity. In addition, measured signal intensity of the white matter was significantly increased in patients compared with controls.. Poor differentiation of gray and white matter on T2-weighted images is the most typical MRI finding of the 18q- syndrome. These results support the postulation that abnormal myelination in 18q- syndrome is due to haploinsufficiency at or near the MBP locus.

Topics: Abnormalities, Multiple; Adolescent; Adult; Brain; Child; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 18; Female; Humans; Infant; Magnetic Resonance Imaging; Male; Myelin Basic Protein

The 18q- deletion syndrome (18qDS) is frequently associated with cardiac anomalies. Patients with this syndrome may also have epilepsy, which presents certain diagnostic difficulties. This case report aims to illustrate these diagnostic problems, document the usefulness of heart rate-based seizure detection algorithms in this setting, and define the epilepsy syndrome associated with 18qDS.. Closed-circuit video electroencephalogram (EEG) monitoring using a heart rate-based seizure detection software was used to identify the event in question and to establish the diagnosis of epilepsy. Chromosomal analysis and magnetic resonance imaging (MRI) were used to further define the epilepsy syndrome.. We report on a patient with an atrial septal defect, enlargement of the right heart, and incomplete right bundle branch block, who developed episodes of tachycardia, loss of consciousness, and pallor, for which he was amnesic. Chromosomal analysis demonstrated karyotype 46,XY,del(18)(q21.3). ish del(18)(wcp18+,D18Z1+) with a loss of the gene for myelin basic protein. MRI revealed multifocal dysmyelination. Video-EEG monitoring using an electrocardiogram (ECG)-triggered seizure detection software proved to be indispensable in detecting an autonomic seizure and establishing the correct diagnosis; the procedure also allowed for the definition of the epilepsy syndrome. The patient was treated with carbamazepine and remained seizure-free.. Video-EEG monitoring using a heart rate-based seizure detection software can be helpful in diagnostically differentiating autonomic seizures from syncope. Dysmyelination due to loss of the myelin basic protein gene on 18q and cortical dysgenesis may be of pathogenic relevance.

Topics: Adult; Autonomic Nervous System Diseases; Chromosome Deletion; Chromosome Mapping; Chromosomes, Human, Pair 18; Demyelinating Diseases; Diagnosis, Differential; Electrocardiography; Electroencephalography; Epilepsy; Heart Defects, Congenital; Humans; Magnetic Resonance Imaging; Male; Monitoring, Physiologic; Myelin Basic Protein; Syncope; Syndrome; Videotape Recording

Topics: Brain; Brain Diseases; Chromosome Deletion; Chromosomes, Human, Pair 18; Demyelinating Diseases; Humans; Magnetic Resonance Imaging; Myelin Basic Protein; Syndrome

Topics: Brain; Brain Diseases; Chromosome Deletion; Chromosomes, Human, Pair 18; Demyelinating Diseases; Humans; Magnetic Resonance Imaging; Myelin Basic Protein; Syndrome

Magnetic resonance imaging (MRI) and MRI relaxometry were used to investigate disturbed brain myelination in 18q- syndrome, a disorder characterized by mental retardation, dysmorphic features, and growth failure. T1-weighted and dual spin-echo T2-weighted MR images were obtained, and T1 and T2 parametric image maps were created for 20 patients and 12 controls. MRI demonstrated abnormal brain white matter in all patients. White matter T1 and T2 relaxation times were significantly prolonged in patients compared to controls at all ages studied, suggesting incomplete myelination. Chromosome analysis using fluorescence in situ hybridization techniques showed that all patients with abnormal MRI scans and prolonged white matter T1 and T2 relaxation times were missing one copy of the myelin basic protein (MBP) gene. The one patient with normal-appearing white matter and normal white matter T1 and T2 relaxation times possessed two copies of the MBP gene. MRI and molecular genetic data suggest that incomplete cerebral myelination in 18q- is associated with haploinsufficiency of the gene for MBP.

Topics: Abnormalities, Multiple; Adolescent; Brain; Brain Diseases, Metabolic; Child; Child, Preschool; Chromosome Aberrations; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 18; Female; Gene Deletion; Humans; In Situ Hybridization, Fluorescence; Infant; Magnetic Resonance Imaging; Male; Myelin Basic Protein; Myelin Sheath; Polymerase Chain Reaction; Syndrome

Growth hormone insufficiency is a common cause of growth failure in children with the 18q- syndrome. Individuals with this syndrome have a deletion as large as 36 Mb from the long arm of chromosome 18. We have evaluated 33 children with this syndrome for growth hormone production and have identified a region of approximately 2 Mb, which is deleted in every growth hormone insufficient patient. Two genes contained in this region, myelin basic protein, and the galanin receptor, are candidate genes for the growth hormone insufficiency phenotype.

Topics: Child; Chromosome Deletion; Chromosome Mapping; Chromosomes, Artificial, Yeast; Chromosomes, Human, Pair 18; Genetic Markers; Growth Disorders; Haplotypes; Human Growth Hormone; Humans; Myelin Basic Protein; Receptors, Galanin; Receptors, Gastrointestinal Hormone

We investigated two short tandem tetranucleotide (TGGA) repeat polymorphisms upstreams of the myelin basic protein (MBP) gene. The region was amplified by the polymerase chain reaction (PCR) and the two repeat systems were separated by cutting with the restriction enzyme NlaIII. The lengths of the DNA fragments were analyzed by vertical electrophoresis in polyacrylamide gels followed by silver staining. We compared the DNA fragment frequencies of the two MBP regions in 34 patients suffering from multiple sclerosis and in 78 suffering from monosymptomatic idiopathic optic neuritis to those in 200 healthy controls. We found no significant differences between the MBP fragment frequencies in either of the patient groups and in the control group.

Topics: Alleles; Chromosome Deletion; Cloning, Molecular; Denmark; DNA; Gene Frequency; Genes; Genetic Predisposition to Disease; Humans; Microsatellite Repeats; Multiple Sclerosis; Myelin Basic Protein; Optic Neuritis; Polymerase Chain Reaction

A Japanese boy with the typical manifestations of 18q-syndrome and delayed myelination on magnetic resonance imaging is described. Cytogenetic investigation revealed a deletion at 18q21.3. Three serial magnetic resonance images demonstrated that myelination in the central nervous system was delayed except for the corpus callosum and brainstem. This pattern of delayed myelination appears to be peculiar to the 18q- syndrome. Because the gene for myelin basic protein has been localized to the distal end of the long arm of chromosome 18, we speculate that the abnormal myelination in our patient was partly due to the failure of expression of the myelin basic protein gene.

Topics: Brain; Brain Stem; Child, Preschool; Chromosome Aberrations; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 18; Corpus Callosum; Demyelinating Diseases; Developmental Disabilities; Glucuronidase; Humans; Magnetic Resonance Imaging; Male; Muscle Hypotonia; Myelin Basic Protein; Neurologic Examination

Human coronaviruses (HCV) are important pathogens responsible for respiratory, gastrointestinal and possibly neurological disorders. To better understand the molecular biology of the prototype HCV-229E strain, the nucleotide sequence of the 5'-unique regions of mRNAs 4 and 5 were determined from cloned cDNAs. Sequence analysis of the cDNAs synthesized from mRNA 4 revealed a major difference with previously published results. However, polymerase chain reaction amplification of this region showed that the sequenced cDNAs were produced from minor RNA species, an indication of possible genetic polymorphism in this region of the viral genome. The mutated messenger RNA 4 contains two ORFs: (1) ORF4a consisting of 132 nucleotides which potentially encodes a 44-amino acid polypeptide of 4653 Da; this coding sequence is preceded by a consensus transcriptional initiation sequence, CUAAACU, similar to the ones found upstream of the N and M genes; (2) ORF4b of 249 nucleotides potentially encoding an 83-amino acid basic and leucine-rich polypeptide of 9550 Da. On the other hand, mRNA 5 contains one single ORF of 231 nucleotides which could encode a 77-amino acid basic and leucine-rich polypeptide of 9046 Da. This putative protein presents a significant degree of amino acid homology (33%) with its counterpart found in transmissible gastroenteritis coronavirus (TGEV). The proteins in the two different viruses exhibit similar molecular weights and are extremely hydrophobic. Interestingly, a sequence homology of five amino acids was found between the protein encoded by ORF4b of HCV-229E and an immunologically important region of human myelin basic protein.

Topics: Amino Acid Sequence; Animals; Base Composition; Base Sequence; Cell Line; Chromosome Deletion; Coronaviridae; Embryo, Mammalian; Humans; Lung; Molecular Sequence Data; Myelin Basic Protein; Open Reading Frames; Polymorphism, Genetic; RNA, Messenger; RNA, Viral; Sequence Homology, Nucleic Acid

We report evoked potential findings in a patient with 18q-syndrome (18q22.3----qter). The deletion included the locus for myelin basic protein (MBP). Clinical manifestations were mild intellectual deficit, involuntary movements and ataxia. MRI of the brain showed diffusely abnormal white matter. Visual evoked responses were normal. Central conduction was prolonged on median somatosensory evoked potentials and no central response was seen with posterior tibial somatosensory potentials. Putative congenital deficiency of MBP does not necessarily cause abnormal visual evoked responses.

Topics: Adult; Cerebral Cortex; Chromosome Deletion; Chromosome Mapping; Chromosomes, Human, Pair 18; Demyelinating Diseases; Electroencephalography; Evoked Potentials, Somatosensory; Evoked Potentials, Visual; Female; Humans; Myelin Basic Protein; Signal Processing, Computer-Assisted

Trophic control over the expression and membrane distribution of voltage-dependent ion channels is one of the principal organizing events underlying the maturation of excitable cells. The myelin sheath is a major structural determinant of regional ion channel topography in central axons, but the exact molecular signals that mediate local interactions between the oligodendrocyte and axolemma are not known. We have found that large caliber fibre pathways in the brain of the mutant mouse shiverer (shi, gene on chromosome 18), whose developmental fate of myelination is averted by deletion of five exons in the myelin basic protein gene, have a striking excess of sodium channels. As cytoplasmic membranes of shiverer oligodendroglia still adhere to axons, the evidence indicates that myelin basic protein or a myelin basic protein-dependent glial transmembrane signal associated with compact myelin formation, rather than a simple glial-axon contact inhibition or an intrinsic genetic program of neuronal differentiation, could be critical in downregulating sodium channel density in axons. Here we use the shiverer mutant to show that mature central nervous system projection neurons with large caliber unmyelinated fibres sustain functional excitability by increasing sodium channel density. This axon plasticity, triggered by the absence of a single glial protein, contributes to the unexpectedly mild degree of neurological impairment in the mutant brain without myelin, and may be a potentially inducible mechanism determining the recovery of function from dysmyelinating disease.

Topics: Animals; Axons; Brain; Cell Membrane; Chromosome Deletion; Demyelinating Diseases; Exons; Mice; Mice, Neurologic Mutants; Myelin Basic Protein; Myelin Sheath; Nerve Fibers; Oligodendroglia; Saxitoxin; Sodium Channels

We have evaluated a young woman with segmental spinal muscular atrophy, who has a deletion of a portion of the long arm of chromosome 18. She also has vitiligo and lichen sclerosis et atrophicus. She has neither the facial dysmorphism nor the mental deficit usually associated with the 18q- syndrome. Magnetic resonance imaging scan of her brain demonstrates high signal intensity consistent with abnormal myelination. Southern blot analysis of her DNA demonstrates that the deletion includes the gene for human myelin basic protein. Neither spinal muscular atrophy nor this patient's skin manifestations have been previously reported in association with 18q-.

Topics: Adult; Brain Diseases; Chromosome Deletion; Chromosomes, Human, Pair 18; DNA; Female; Humans; Karyotyping; Magnetic Resonance Imaging; Muscular Atrophy, Spinal; Myelin Basic Protein; Scleroderma, Localized; Vitiligo

We describe the measurement of myelin basic protein gene transcription rate, and of the accumulation of both mature mRNA and total transcripts from the myelin basic protein gene in brains from mice of wild-type and homozygous shiverer genotypes at several ages spanning postnatal development. In wild-type brains the accumulation of total transcripts as well as mature mRNA, and the transcription rate, all follow the same general pattern of rising sharply from a low level at birth to a peak at 20 days, and continuing at a somewhat reduced level into adulthood. Thus a major factor in the developmental regulation of myelin basic protein expression is the control of transcription rate. The shiverer mutation consists of a deletion of the 3' end of the myelin basic protein gene which completely prevents production of mature mRNA and protein, and results in severe dysmyelination and a trembling behavior. In shiverer brains, the transcription rates for the intact 5' end of the gene follow closely those seen in wild-type animals up to the age at which maximal myelination normally occurs. Total myelin basic protein transcripts follow a similar profile but at less than 5% the level seen in wild-type, and, as expected, no mature mRNA is detected. Thus the shiverer deletion does not remove information required for efficient, developmentally regulated transcription, and the low level of myelin basic protein gene transcripts in this mutant must be a result of their reduced stability. A higher than normal myelin basic protein gene transcription rate in older shiverer animals raises interesting questions regarding the regulatory mechanisms controlling myelinogenesis.

Topics: Animals; Brain Chemistry; Chromosome Deletion; Demyelinating Diseases; Gene Expression Regulation; Mice; Mice, Neurologic Mutants; Myelin Basic Protein; Promoter Regions, Genetic; RNA, Messenger; Transcription, Genetic

Protein tyrosine phosphorylation is regulated by both protein tyrosine kinases and protein tyrosine phosphatases (PTPases). Recently, the structures of a family of PTPases have been described. In order to study the structure-function relationships of receptor-linked PTPases, we analyzed the effects of deletion and point mutations within the cytoplasmic region of the receptor-linked PTPases, LCA and LAR. We show that the first of the two domains has enzyme activity by itself, and that one cysteine residue in the first domain of both LCA and LAR is absolutely required for activity. The second PTPase like domains do not have detectable catalytic activity using a variety of substrates, but sequences within the second domains influence substrate specificity. The functional significance of a stretch of 10 highly conserved amino acid residues surrounding the critical cysteine residue located in the first domain of LAR was assessed. At most positions, any substitution severely reduced enzyme activity, while missense mutations at the other positions tested could be tolerated to varying degrees depending on the amino acid substitution. It is suggested that this stretch of amino acids may be part of the catalytic center of PTPases.

Topics: Amino Acid Sequence; Animals; Antigens, Differentiation; Base Sequence; Binding Sites; Cattle; Cell Adhesion Molecules; Chromosome Deletion; Histocompatibility Antigens; Leukocyte Common Antigens; Membrane Glycoproteins; Molecular Sequence Data; Mutation; Myelin Basic Protein; Phosphoprotein Phosphatases; Plasmids; Protein Tyrosine Phosphatases; Restriction Mapping

We report a mother and son with a deletion at 18q22.3. Both have the typical manifestations of the 18q- syndrome. In addition, both have an action tremor which became apparent in childhood. The mother subsequently developed chorea and dysmetria in late adolescence. Magnetic resonance imaging of their brains showed poor myelination of the central white matter tracts with relatively normal myelination of the corpus callosum. We propose that these neurologic findings are most likely due to a failure of expression of the myelin basic protein gene.

Topics: Abnormalities, Multiple; Adult; Brain; Chromosome Deletion; Chromosomes, Human, Pair 18; Ear; Female; Humans; Infant; Magnetic Resonance Imaging; Male; Myelin Basic Protein; Tremor

We measured transiently-expressed beta-galactosidase activity by introducing the mouse myelin basic protein (MBP)-lacZ chimeric gene (MBP-lacZ) into the NG108-15 neuronal/glial hybrid cell line. Deletion studies of the promoter region of the MBP gene showed that the promoter region between -1318 bp and -254 bp might contain sequences that repress MBP promoter activity. Fine deletion analysis using BAL 31 exonuclease revealed sequences between bp -208 and -140, -139 and -118, and -89 and -75 which were critical for promoter activity in NG 108-15 cells. DNaseI footprinting analysis revealed a cellular factor(s) that bind to the promoter region between bp -127 and -106 with NG108-15 whole cell extracts. The SV40 promoter was activated by insertion of the sequences around the region protected in footprinting experiments, in a manner independent of its orientation in NG108-15 cells. This protected region is thought to be one of the critical cis-acting DNA elements for efficient transcription.

Topics: Animals; Base Sequence; beta-Galactosidase; Cell Line; Chimera; Chromosome Deletion; Deoxyribonuclease I; Hybrid Cells; Mice; Molecular Sequence Data; Myelin Basic Protein; Promoter Regions, Genetic; Simian virus 40; Transcription, Genetic; Transfection

A minigene containing mouse cDNA coding for the smallest type of myelin basic protein and including the native promoter was constructed and used to produce transgenic shiverer mice. The hypomyelinating mouse, the shiverer, has a deletion in its myelin basic protein gene, lacks all four types of myelin basic protein in its myelin, and shows abnormal behavior such as violent tremors. Five of twenty-one transgenic shiverer mice showed recovered protein synthesis, compact myelin formation, and normal behavior. These results suggest that a single type of myelin basic protein restores myelin formation and returns the shivering phenotype to normal in the transgenic shiverer mouse.

Topics: Animals; Base Sequence; Cerebellum; Chromosome Deletion; Female; Genes; Immunoenzyme Techniques; Mice; Mice, Neurologic Mutants; Mice, Transgenic; Microscopy, Electron; Molecular Sequence Data; Myelin Basic Protein; Myelin Sheath; Plasmids

A hereditary dysmyelination mutation, named myelin deficient (mld), is considered to be allelic to shiverer, a deletion mutation of the myelin basic protein (MBP) gene. The present study showed that MBP expression is greatly reduced in mld, but that it is still detectable. Northern blot analysis revealed that the pronounced decrease in the MBP level in mld resulted from a reduced mRNA level and was not caused by deletion of a large portion of the MBP gene as in shiverer. Southern blot studies with BamHI-digested chromosomal DNA suggested some part of the MBP gene, at least the 5'-portion, was duplicated in mld. These results indicated that the mld and shiverer mutations were different from each other, even though genetic allelism between the two was reconfirmed. We also examined the developmental pattern of the gene expression of MBP and that of another protein, myelin proteolipid protein (PLP), specifically expressed in the oligodendrocyte, in mld by RNA dot blot study. The mRNA level of MBP in mld was greatly reduced during the active myelination stages, gradually increasing and remaining constant in the later stages. The PLP-mRNA content in mld was almost normal (60-80% that of control) at any stage of development. All these findings imply that the primary defect in mld is due to reduced transcriptional activity of the MBP gene.

Topics: Alleles; Animals; Chromosome Deletion; Deoxyribonuclease BamHI; Deoxyribonuclease HindIII; Deoxyribonucleases, Type II Site-Specific; DNA Restriction Enzymes; Gene Expression Regulation; Mice; Mice, Mutant Strains; Myelin Basic Protein; Nucleic Acid Hybridization; RNA, Messenger; Transcription, Genetic

Mice homozygous for the autosomal recessive mutation shiverer (shi) lack myelin basic protein (MBP) and exhibit a distinct behavioral pattern including tremors (shivering), convulsions, and early death. We have previously demonstrated that shiverer mice have a partial deletion in the gene encoding MBP. We now have introduced the wild-type MBP gene into the germ line of shiverer mice by microinjection into fertilized eggs. Transgenic shiverer mice homozygous for the introduced gene have MBP mRNA and protein levels that are approximately 25% of normal, and produce compacted myelin with major dense lines. Correct temporal and spatial expression of the MBP gene is achieved with a genomic MBP cosmid clone containing 4 kb of 5' flanking sequence and 1 kb of 3' flanking sequence. Moreover, the four different forms of MBP produced by alternative patterns of RNA splicing are present. These homozygous transgenic shiverer mice no longer shiver nor die prematurely.

Topics: Alleles; Animals; Base Sequence; Chromosome Deletion; Gene Expression Regulation; Homozygote; Mice; Mice, Quaking; Microinjections; Microscopy, Electron; Myelin Basic Protein; Optic Nerve; Pedigree; Phenotype

Shiverer (shi) is an autosomal recessive mutation in the mouse characterized by an almost total lack of central nervous system myelin. While small amounts of other myelin components are present in the brain of the shi mouse, the four forms of myelin basic protein (MBP) are not detectable. Previous investigations by us and others indicate that the MBP gene has undergone a major rearrangement in the shi mutant. Herein, we report in detail the nature and extent of the rearrangement: a 20-kilobase region within the MBP gene is missing in the mutant. We map the 5' breakpoint of the deletion to the second intron and the 3' breakpoint to a site 2 kilobases beyond the last MBP exon. The junction of the upstream and downstream portions of the gene contains only one nucleotide not accounted for by the wild-type MBP gene sequence. The 3' side of the deletion occurs in the 3rd of 11 tandem repeats of a 31-base-pair sequence. This region is rich in alternating purine and pyrimidine stretches, sequences that have been associated with both Z-DNA structures and gene rearrangements. The recombination junction shares several features with the junctions characterized by Anderson et al. [Anderson, R., Kato, S. & Camerini-Otero, D. (1984) Proc. Natl. Acad. Sci. USA 81, 206-210] in mouse L cells and is consistent with their model for a partially homologous recombination event. The structure of the shi recombination junction suggests that the donor DNA molecules were aligned in a partially homologous region before staggered cutting and joining occurred.

Topics: Animals; Base Sequence; Chromosome Deletion; Chromosome Mapping; Genes; Mice; Mice, Neurologic Mutants; Myelin Basic Protein; Recombination, Genetic

The gene for mouse myelin basic protein (MBP) was mapped to chromosome 18 by hybridization of cloned MBP probes to DNA from hamster-mouse hybrid cell lines, showing it to be linked to the shiverer mutation which causes abnormal CNS myelination. Genomic blotting experiments show that in the mutants five of six exons which constitute the wild-type gene have been deleted. In shiverer brains the steady state level of transcripts that initiate correctly at the 5' end of the remaining exon 1 is reduced 16-fold. These RNAs are not spliced correctly and are not efficiently polyadenylated. It is proposed that the partial deletion of the MBP gene is an important part of the shiverer lesion.

Topics: Animals; Base Sequence; Brain; Chromosome Deletion; Chromosome Mapping; Genes; Genetic Linkage; Mice; Mice, Neurologic Mutants; Mutation; Myelin Basic Protein; Poly A; RNA Splicing; RNA, Messenger; Transcription, Genetic

The gene expression of myelin basic proteins (MBPs) in shiverer mutant mice was investigated by the Northern and Southern hybridization techniques. In the control mice RNA molecules from the brains which were about 2,300 nucleotides in length were hybridized to cDNA of 1.8 kb encoding for a mouse MBP, but RNA from the brains of 3-week-old shiverer mutant mice contained no detectable amount of MBP transcripts hybridizing to this probe. Moreover the shiverer mutant mice lost several restriction fragments that hybridized to the same probe in the control mice when each of the five restriction enzymes, i.e., HindIII, PstI, PvuII, AccI, and StuI, was used. These data suggest that the shiverer mutation may correspond to the deletion of a large portion of MBP exon(s) in the gene, and this deletion causes inefficient transcription leading to the depletion of MBPs in the myelin and the dysmyelination observed in these mice.

Topics: Animals; Chromosome Deletion; DNA; DNA Restriction Enzymes; Gene Expression Regulation; Mice; Mice, Inbred C3H; Mice, Neurologic Mutants; Myelin Basic Protein; Transcription, Genetic

Topics: Animals; Antigens; Autoantigens; Biological Evolution; Chromosome Deletion; Epitopes; Genes; Immune Tolerance; Immunoglobulin Variable Region; Myelin Basic Protein; Thyroglobulin