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L Ozelius

Publications and source records attributed to L Ozelius.

At least 37 records · Page 2Linked to original sources
PubMed1992

Construction of a GT polymorphism map of human 9q.

To construct a framework map of human chromosome 9 consisting of highly informative markers, we identified 36 cosmid clones from chromosome 9 that contained long GT repeat sequences. The cosmids were found to cluster on the long arm of the chromosome, particularly in the q32-34 region. Thirteen highly informative polymorphisms from 9q were identified, with median observed heterozygosity 0.75 and median calculated heterozygosity based upon allele frequencies of 0.75. These new GT repeat polymorphisms (D9S56, D9S58-67), as well as anchor GT polymorphisms for D9S15 (MCT112, 9q13), and ABL and ASS (both 9q34.1) were utilized to construct a linkage map of human 9q by the typing of the Venezuelan Reference Pedigree. Care was taken to avoid errors, including analysis of the data with CHROMLOOK and verification of all double crossover events detected within a 30 cM interval by repetition of the marker analysis. The map was generated using the MAPMAKER program. All positions in the resulting map are favored by odds of greater than 10(4):1. The map has a sex-averaged length of 90 cM (Kosambi function) with a single maximum intermarker recombination fraction of 26%. All other intermarker recombination fractions are less than 15%. As D9S15 is known to be closely linked to markers on proximal 9p, and ASS/ABL are in band 34.1, this set of GT polymorphisms spans the length of 9q and provides a useful panel for linkage analysis of disease genes to this region. The marker order was confirmed by in situ hybridization of the cosmid clones to metaphase spreads of normal human chromosomes, which indicated an excess of recombination in the telomeric region in comparison to centromeric 9q, in agreement with previous chiasmata distribution observations. Two spontaneous new mutations for these GT repeat markers were identified, giving an overall observed spontaneous mutation rate of 0.00045 per locus per gamete. Direct observation of new mutations has not been previously reported for dinucleotide polymorphisms, but the observed rate is consistent with frequencies observed for other VNTR polymorphisms.

Base Sequence↗
PubMed1992

A syndrome of autosomal dominant alternating hemiplegia: clinical presentation mimicking intractable epilepsy; chromosomal studies; and physiologic investigations.

We report the familial occurrence and apparent autosomal dominant inheritance of alternating hemiplegia of childhood. The proband, a 9-year-old boy, presented with developmental retardation, rare tonic-clonic seizures, and frequent episodes of flaccid alternating hemiplegia that had been presumed to represent postictal paralysis. The hemiplegia spells, which started in his first year, did not respond to multiple antiepileptics. Between attacks, there was choreoathetosis and dystonic posturing. Father, brother, paternal uncle, and paternal grandmother had similar histories of alternating hemiplegia. Investigations included negative CT, metabolic, and coagulation studies. EEG and SPECT 99mTc exametazime scanning failed to reveal any significant slowing or any major changes in cortical perfusion during hemiplegia as compared with nonhemiplegic periods. The karyotype revealed a balanced reciprocal translocation, 46,XY,t(3;9)(p26;q34) in the patient, in all the affected living relatives, and in one apparently unaffected sibling. The asymptomatic mother had a normal karyotype. Analysis of DNA markers was consistent with the karyotype results. Both affected siblings were treated with and responded to flunarizine therapy, with a greater than 70% decrease in attack frequency. Documented flunarizine trough serum concentrations were 28.9 ng/ml in the proband and 6.6 ng/ml in his brother.

Adult↗
PubMed1991

Dopamine beta-hydroxylase gene excluded in four subtypes of hereditary dystonia.

The hereditary dystonias include a clinically heterogeneous group of movement disorders varying in symptoms, age of onset, and drug responsiveness. Dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine, has been implicated in dystonia because of increased serum levels of DBH in some patients, the influence of catecholaminergic drugs on the human phenotypes, and altered norepinephrine levels in several brain regions in dystonia patients and in genetically dystonic rodents. In addition, markers linked to the dystonia gene in two ethnic groups map close to the DBH locus on human chromosome 9q34. Here we evaluate the inheritance of restriction fragment length polymorphisms near the DBH gene in families with four subtypes of hereditary dystonia: Jewish and non-Jewish, early onset, generalized idiopathic torsion dystonia (ITD); dopa-responsive dystonia; and myoclonic dystonia. In all families, obligate recombination events were observed between the DBH and dystonia genes, thus excluding the DBH gene as the primary defect.

Adolescent↗
PubMed1991

Torsion dystonia genes in two populations confined to a small region on chromosome 9q32-34.

Idiopathic torsion dystonia (ITD) is characterized by sustained, involuntary muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. Most familial forms of ITD display autosomal dominant inheritance with reduced penetrance. Linkage analysis has been previously used to localize a dystonia gene to the 9q32-34 region in a large non-Jewish family and in a group of Ashkenazi Jewish families. Utilizing GT repeat polymorphisms from this region, here we demonstrate that the gene causing dystonia in Ashkenazi Jews can be localized to the 11-cM interval between AK1 and D9S10. Linkage analysis in the non-Jewish family is also consistent with occurrence of the gene in this region, although positive lod scores extend over a greater than 20-cM interval in that family. These results set the stage for positional cloning of the dystonia gene. Currently there are no known candidate genes in this region.

Base Sequence↗
PubMed1991

Identification of a highly polymorphic microsatellite VNTR within the argininosuccinate synthetase locus: exclusion of the dystonia gene on 9q32-34 as the cause of dopa-responsive dystonia in a large kindred.

Dopa-responsive dystonia is a clinical variant of idiopathic torsion dystonia that is distinguished from other forms of dystonia by the frequent occurrence of parkinsonism, diurnal fluctuation of symptoms, and its dramatic therapeutic response to L-dopa. Linkage of a gene causing classic dystonia in a large non-Jewish kindred (DYT1) and in a group of Ashkenazi Jewish families, to the gelsolin (GSN) and arginino-succinate synthetase (ASS) loci on chromosome 9q32-34, respectively, was recently determined. Here we report the discovery of a highly informative (GT)n repeat VNTR polymorphism within the ASS locus. Analysis of a large kindred with dopa-responsive dystonia, using this new polymorphism and conventional RFLPs for the 9q32-34 region, excludes loci in this region as a cause of this form of dystonia. This provides proof of genetic heterogeneity between classic idiopathic torsion dystonia and dopa-responsive dystonia.

Argininosuccinate Synthase↗
PubMed1990

Dystonia gene in Ashkenazi Jewish population is located on chromosome 9q32-34.

Idiopathic torsion dystonia (ITD) is a neurological disorder characterized by sustained muscle contractions that appear as twisting movements of the limbs, trunk, and/or neck, which can progress to abnormal postures. Most familial forms of ITD follow autosomal dominant transmission with reduced penetrance. The frequency of ITD in the Ashkenazi Jewish population is five to ten times greater than that in other groups. Recently, a gene for ITD (DYT1) in a non-Jewish kindred was located on chromosome 9q32-34, with tight linkage to the gene encoding gelsolin (GSN). In the present study linkage analysis using DNA polymorphisms is used to locate a gene responsible for susceptibility to ITD in 12 Ashkenazi Jewish families. This dystonia gene exhibits close linkage with the gene encoding argininosuccinate synthetase (ASS), and appears by multipoint analysis to lie in the q32-34 region of chromosome 9, a region that also contains the loci for gelsolin and dopamine-beta-hydroxylase. The same gene may be responsible for ITD both in the non-Jewish kindred mentioned above and in the Ashkenazi Jewish families presented here. However, because there is substantial difference between the penetrance of the dominant allele in these two groups, two different mutations may be operating to produce susceptibility to this disease in the two groups.

Adolescent↗
PubMed1989

Human gene for torsion dystonia located on chromosome 9q32-q34.

Torsion dystonia is a movement disorder of unknown etiology characterized by loss of control of voluntary movements appearing as sustained muscle contractions and/or abnormal postures. Dystonic movements can be caused by lesions in the basal ganglia, drugs, or gene defects. Several hereditary forms have been described, most of which have autosomal dominant transmission with variable expressivity. In the Ashkenazi Jewish population the defective gene frequency is about 1/10,000. Here, linkage analysis using polymorphic DNA and protein markers has been used to locate a gene responsible for susceptibility to dystonia in a large, non-Jewish kinship. Affected members of this family have a clinical syndrome similar to that found in the Jewish population. This dystonia gene (ITD1) shows tight linkage with the gene encoding gelsolin, an actin binding protein, and appears by multipoint linkage analysis to lie in the q32-q34 region of chromosome 9 between ABO and D9S26, a region that also contains the locus for dopamine-beta-hydroxylase.

Calcium-Binding Proteins↗
PubMed1989

Monoamine oxidase deficiency in males with an X chromosome deletion.

Mapping of the human MAOA gene to chromosomal region Xp21-p11 prompted our study of two affected males in a family previously reported to have Norrie disease resulting from a submicroscopic deletion in this chromosomal region. In this investigation we demonstrate in these cousins deletion of the MAOA gene, undetectable levels of MAO-A and MAO-B activities in their fibroblasts and platelets, respectively, loss of mRNA for MAO-A in fibroblasts, and substantial alterations in urinary catecholamine metabolites. The present study documents that a marked deficiency of MAO activity is compatible with life and that genes for MAO-A and MAO-B are near each other in this Xp chromosomal region. Some of the clinical features of these MAO deletion patients may help to identify X-linked MAO deficiency diseases in humans.

Adolescent↗
PubMed1989

Norrie disease gene is distinct from the monoamine oxidase genes.

The genes for MAO-A and MAO-B appear to be very close to the Norrie disease gene, on the basis of loss and/or disruption of the MAO genes and activities in atypical Norrie disease patients deleted for the DXS7 locus; linkage among the MAO genes, the Norrie disease gene, and the DXS7 locus; and mapping of all these loci to the chromosomal region Xp11. The present study provides evidence that the MAO genes are not disrupted in "classic" Norrie disease patients. Genomic DNA from these "nondeletion" Norrie disease patients did not show rearrangements at the MAOA or DXS7 loci. Normal levels of MAO-A activities, as well as normal amounts and size of the MAO-A mRNA, were observed in cultured skin fibroblasts from these patients, and MAO-B activity in their platelets was normal. Catecholamine metabolites evaluated in plasma and urine were in the control range. Thus, although some atypical Norrie disease patients lack both MAO-A and MAO-B activities, MAO does not appear to be an etiologic factor in classic Norrie disease.

Blood Platelets↗
PubMed1988

Partial linkage map of chromosome 13q in the region of the Wilson disease and retinoblastoma genes.

Genetic linkage maps are useful tools for defining the location of disease genes. Previously published maps of human chromosome 13 have been incomplete and have had ambiguities of order in the vicinity of the Wilson disease (WND) and retinoblastoma (RB1) genes. We have defined a six-locus map of this region using a large reference pedigree from Venezuela. Our map provides landmarks which will aid in the localization of WND, in determining the extent of deletions in retinoblastoma, and in the mapping of other marker loci.

Chromosome Mapping↗