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Biomedical subjects

Lars Forsgren

Publications and source records attributed to Lars Forsgren.

11 recordsLinked to original sources
PubMed2005

Exclusion of the juvenile myoclonic epilepsy gene EFHC1 as the cause of migraine on chromosome 6, but association to two rare polymorphisms in MEP1A and RHAG.

Migraine is a complex, multifactorial disorder for which several loci have been identified in the human genome. We have previously reported linkage to a 10 Mb-region on chromosome 6p12.2-p21.1 in one large Swedish pedigree involving migraine with and without aura. To further investigate this candidate region, a dense set of single nucleotide polymorphic (SNP) markers was used for fine-mapping, decreasing the critical region to 8.5 Mb. Within this region, EFHC1 was recently identified as the disease gene for juvenile myoclonic epilepsy. Migraine and epilepsy has been suggested to share disease mechanisms and therefore EFHC1 is an excellent candidate gene for migraine in this family. Mutation analysis of the gene revealed a disease-segregating polymorphism in the promoter. Association analysis of the polymorphism in a case-control material did not support a role for this gene in migraine pathology. We therefore analyzed five additional candidate genes in the disease-critical region, including MEP1A, RHAG, IL17, SLC25A27 and TNFRSF21. In two of these genes, MEP1A and RHAG, we identified two novel polymorphisms associated with the disease haplotype. The combination of these polymorphisms could not be found in any control individuals, suggesting that they might be involved in genetic predisposition to migraine in this family.

Blood Proteins↗
PubMed2005

Identification and characterization of Spinocerebellar Ataxia Type 7 (SCA7) isoform SCA7b in mice.

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease primarily affecting the cerebellum, brainstem and retina. The disease is caused by a polyglutamine expansion in ataxin-7, a protein with largely unknown function. To improve our knowledge of the expression and function of wild-type and expanded ataxin-7, we looked for alternative SCA7 transcripts in mice. We identified a murine SCA7 isoform (SCA7b) containing an uncharacterized exon homologous to the newly identified human exon 12b. Northern blot analysis revealed three exon 12b containing transcripts with molecular sizes of 7.5, 4.4 and 3.0 kb in mice. This contrasted with the situation in humans, where only one exon 12b-containing transcript was observed. Furthermore, Northern blot of the human 4.4 kb SCA7b isoform predominantly showed expression in the brain, while expression of both the murine 7.5-kb and the 4.4-kb transcripts were observed in several tissues including brain, heart, liver, kidney and testis. Quantitative real-time RT-PCR analysis revealed that in muscle and heart SCA7b is the predominant SCA7 isoform, while in brain equal levels of SCA7a and SCA7b was observed. Insertion of exon 12b into the murine SCA7 ORF resulted in a frame-shift that gave rise to an alternative ataxin-7 protein (ataxin-7b). The novel 58-amino acid C-terminus in ataxin-7b directed the protein to a more cytoplasmic location.

Alternative Splicing↗
PubMed2005

A role for both wild-type and expanded ataxin-7 in transcriptional regulation.

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease primarily affecting the brainstem, retina and Purkinje cells of the cerebellum. The disease is caused by a polyglutamine expansion in ataxin-7, a protein found in two complexes TFTC and STAGA, involved in transcriptional regulation. Transcriptional dysregulation has been implicated in the pathology of several polyglutamine diseases. In this paper, we analyzed the effect of both wild-type and expanded ataxin-7 on transcription driven by the co-activator CBP and the Purkinje cell expressed nuclear receptor RORalpha1. We could show that transcription mediated by both CBP and RORalpha1 was repressed by expanded ataxin-7. Interestingly, repression of transcription could also be observed with wild-type full-length ataxin-7, not only on CBP- and RORalpha1-mediated transcription, but also on basal transcription. The repression could be counteracted by inhibition of deacetylation, suggesting that ataxin-7 may act as a repressor of transcription by inhibiting the acetylation activity of TFTC and STAGA.

Acetylation↗
PubMed2005

Mortality of epilepsy in developed countries: a review.

Mortality in people with epilepsy has been studied in many different populations. In population-based incidence cohorts of epilepsy with 7-29 years follow-up, there was up to a threefold increase in mortality, compared to the general population (standardized mortality ratios [SMR] ranged from 1.6 to 3.0). When studies include selected epilepsy populations where patients with frequent and severe seizures are more common, the mortality is even greater. Relative survivorship (RS) following the diagnosis of epilepsy was 91%, 85%, and 83% after 5, 10, and 15 years, respectively. In a population with childhood-onset epilepsy, RS was 94% and 88% after 10 and 20 years. The level of increased mortality is affected by several factors. In idiopathic epilepsy where the causes of seizures are unknown, the results are conflicting. There was no significant increase in mortality in studies from Iceland, France, and Sweden, a barely increased risk in a study from the United Kingdom, and a significantly increased risk in a study from the United States. In contrast, all studies report a significant increased mortality in remote symptomatic epilepsy (standardized mortality ratios [SMRs] ranging from 2.2 to 6.5). The highest mortality is found in patients with epilepsy and neurodeficits present since birth, including mental retardation or cerebral palsy (SMRs ranging from 7 to 50). Mortality is also affected by age, with the highest SMRs in children, the combined effect of low mortality in the reference population, and high mortality in children with neurodeficits and epilepsy. The highest excess mortality is found in the elderly, > or =75 years. A pronounced increase in mortality is found during the first year following the onset of seizures due to underlying severe diseases. The increased mortality remains in different studies 2-14 years following diagnosis. Most of the factors responsible for the increased mortality are related to the underlying disorder causing epilepsy with pneumonia, cerebrovascular disease, and neoplastic disorders (risk remains elevated when primary brain tumors are excluded), as the most frequently recorded causes. The most common direct seizure-related cause of death in adolescents and young adults is sudden unexpected death, which is 24 times more common than in the general population.

Adolescent↗
PubMed2002

Expression of ataxin-7 in CNS and non-CNS tissue of normal and SCA7 individuals.

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder primarily affecting the cerebellum, brain stem and retina. The disease is caused by an expanded polyglutamine tract in the protein ataxin-7. In this study we analyzed the expression pattern of ataxin-7 in CNS and non-CNS tissue from three SCA7 patients and age-matched controls. SCA7 is a rare autosomal dominant disorder, limiting the number of patients available for analysis. We therefore compiled data on ataxin-7 expression from all SCA7 patients (n=5) and controls (n=7) published to date, and compared with the results obtained in this study. Expression of ataxin-7 was found in neurons throughout the CNS and was highly abundant in Purkinje cells of the cerebellum, in regions of the hippocampus and in cerebral cortex. Ataxin-7 expression was not restricted to regions of pathology, and there were no apparent regional differences in ataxin-7 expression patterns between patients and controls. The subcellular distribution of ataxin-7 was primarily nuclear in all brain regions studied. In cerebellar Purkinje cells, however, differences in subcellular distribution of ataxin-7 were observed between patients and controls of different ages. Here we provide an increased understanding of the distribution of ataxin-7, and the possible implication of subcellular localization of this protein on disease pathology is discussed.

Adult↗
PubMed2002

Cloning and expression analysis of the murine homolog of the spinocerebellar ataxia type 7 (SCA7) gene.

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease caused by the expansion of a polyglutamine tract in the protein ataxin-7, a protein of unknown function. In order to analyze the expression pattern of wild type ataxin-7 in detail, the murine SCA7 gene homolog was cloned and the expression pattern in mice analyzed. The SCA7 mouse and human gene exhibit a high degree of identity at both DNA (88.2%) and protein (88.7%) level. The CAG repeat region, known to be polymorphic in man, is conserved in mouse but contained only five repeats in all mouse strains analyzed. The arrestin homology domain and the nuclear localization signal found in human ataxin-7 is also conserved in the murine homolog. Expression of ataxin-7 was detected during mouse embryonic development and in all adult mouse tissues examined by northern and western blots. In brain, immunohistological staining revealed an ataxin-7 expression pattern similar to that in human, with ataxin-7 expression in cerebellum, several brainstem nuclei, cerebral cortex and hippocampus. Our data show high conservation of ataxin-7 both structurally and at the level of expression, suggesting a conserved role for the protein in mice and humans.

Amino Acid Sequence↗
PubMed2002

Sharing of a conserved haplotype suggests a susceptibility gene for multiple sclerosis at chromosome 17p11.

Multiple sclerosis (MS) is a chronic inflammatory disease resulting in demyelination in the central nervous system (CNS). Increasing evidence supports that genetic factors confer susceptibility to MS. One locus, the HLA complex (6p21), has been identified as important in MS, but no other loci have been clearly implicated, neither by a candidate gene approach, nor by a genomic screen strategy. Here, we studied a genetically isolated population in the northern-most part of Sweden, which demonstrates a high incidence of MS, using haplotype sharing analysis. Genealogical analysis demonstrated that 22 MS patients originate from a single common ancestral couple in the eighteenth century. Five affected individuals from four nuclear families were selected for an initial genomic screen with 390 microsatellite markers. Seven shared haplotypes in six different chromosomal regions were observed. After genotyping for these haplotypes with the same and additional markers in 15 MS patients and healthy relatives, some portion of a conserved haplotype spanning 10 cM at 17p11 was found to be shared by 12 of 15 affected individuals. The statistical analysis revealed a significant excess of transmission of alleles of three markers to affected individuals (P<0.05) by the transmission/disequilibrium test (TDT). An identical four-marker haplotype was shared by six of 15 patients (40%; P<0.01). Surprisingly, DR-typing revealed no significant sharing of the HLA region. In conclusion, our data suggests a novel susceptibility gene for MS in chromosome 17p11.

Chromosomes, Human, Pair 17↗
PubMed2002

Socioeconomic prognosis after a newly diagnosed unprovoked epileptic seizure in adults: a population-based case-control study.

PURPOSE: To investigate the socioeconomic prognosis after a newly diagnosed unprovoked epileptic seizure in adults. METHODS: Sixty-three patients 17 years or older with a newly diagnosed unprovoked epileptic seizure from 1985 through 1987 and 107 sex- and age- matched controls were followed up for 10 years to 1996. Studied variables were income, source of income, sickness periods, incapacity rate, diagnosis-specific incapacity rate, vocational status, and education. RESULTS: Relative growth of income was similar between patients and controls during follow-up. Patients had lower income than did controls 2 years before seizure onset and during the entire follow-up. This was related to higher morbidity among patients, as measured by sickness periods and incapacity rate. Employment rates did not evolve negatively among patients after seizure onset and were close to employment rates of controls during follow-up time. There was no difference between patients and controls regarding education. CONCLUSIONS: After a newly diagnosed unprovoked epileptic seizure in adults, no negative development regarding employment and education occurs. Income development is positive unless refractory seizures evolve. However, income is lower among patients with epilepsy than among controls, and this difference can be related to overall morbidity.

Adolescent↗