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M Schalling

Publications and source records attributed to M Schalling.

At least 19 recordsLinked to original sources
PubMed2003

Association between depressed mood in the elderly and a 5-HTR2A gene variant.

The aim of this study was to investigate any possible association between depressed mood in the elderly and two candidate SNPs in the serotonin system: one in the 5-HTR2A gene promotor (-1438 G/A) and one in the 5-HT transporter gene (-925 C/A). DNA from a population-based Swedish twin sample (N = 1,592; mean age = 73) was genotyped using Pryosequencing trade mark. An association was found between the 5-HTR2A gene promotor polymorphism and depressed mood (OR: 1.5, CI: 1.1-2.1) for the A/A genotype in the total sample. When the sample was analyzed by gender, a significant association (OR: 2.4, CI: 1.4-4.4) was found for males and the A/A genotype, but not for females. The 5-HT transporter gene was not associated with depressed mood in this elderly population. These results suggest that there might be different genetic mechanisms for males and females contributing to the development of depressed mood in the elderly.

Aged↗
PubMed2003

The serotonin transporter promoter repeat length polymorphism, seasonal affective disorder and seasonality.

BACKGROUND: Conflicting results have been reported in previous association studies of the serotonin transporter promoter repeat length polymorphism (5-HTTLPR), seasonal affective disorder (SAD) and seasonality (seasonal variations in mood and behaviour). The aim of this study was to test for association in new case-control and population-based materials, and to perform a combined analysis of all published studies of 5-HTTLPR and SAD. METHOD: One hundred and forty-seven new SAD cases and 115 controls were genotyped for 5-HTTLPR and in total 464 patients and 414 controls were included in the pooled analysis. In addition, 226 individuals selected for unusually high or low seasonality scores from a population based material and 46 patients with non-seasonal depression were analysed. Different genetic models were tested and seasonality was analysed both as a qualitative (high v. low) and as a quantitative trait in the different sample sets. RESULTS: No association between 5-HTTLPR and SAD was found in the new case-control material, in the combined analysis of all samples, or when only including 316 patients with controls (N = 298) selected for low seasonality. A difference was detected between the population based high and low seasonality groups, when assuming a recessive effect of the short allele (20% and 10% short allele homozygotes, respectively, OR (95% CI): 2.24 (1.03-4.91)). Quantitative analysis of seasonality revealed no association with 5-HTTLPR in any sample set. CONCLUSIONS: These results do not suggest a major role of the short variant of 5-HTTLPR in susceptibility to SAD, but provide modest evidence for an effect on seasonality.

Adult↗
PubMed2002

Spastic paraplegia, ataxia, mental retardation (SPAR): a novel genetic disorder.

OBJECTIVE: To describe a kindred with a dominantly inherited neurologic disorder manifested either as uncomplicated spastic paraplegia or ataxia, spastic paraplegia, and mental retardation. METHODS: Neurologic examinations and molecular genetic analysis (exclusion of known SCA and HSP genes and loci; and trinucleotide repeat expansion detection [RED]) were performed in six affected and four unaffected subjects in this family. MRI, electromyography (EMG), and nerve conduction studies were performed in three affected subjects. RESULTS: The phenotype of this dominantly inherited syndrome varied in succeeding generations. Pure spastic paraplegia was present in the earliest generation; subsequent generations had ataxia and mental retardation. MRI showed marked atrophy of the spinal cord in all patients and cerebellar atrophy in those with ataxia. Laboratory analysis showed that the disorder was not caused by mutations in genes that cause SCA-1, SCA-2, SCA-3, SCA-6, SCA-7, SCA-8, and SCA-12; not linked to other known loci for autosomal dominant ataxia (SCA-4, SCA-5, SCA-10, SCA-11, SCA-13, SCA-14, and SCA-16); and not linked to known loci for autosomal dominant hereditary spastic paraplegia (HSP) (SPG-3, SPG-4, SPG-6, SPG-8, SPG-9, SPG-10, SPG-12, and SPG-13) or autosomal recessive HSP SPG-7. Analysis of intergenerational differences in age at onset of symptoms suggests genetic anticipation. Using RED, the authors did not detect expanded CAG, CCT, TGG, or CGT repeats that segregate with the disease. CONCLUSIONS: The authors describe an unusual, dominantly inherited neurologic disorder in which the phenotype (pure spastic paraplegia or spastic ataxia with variable mental retardation) differed in subsequent generations. The molecular explanation for apparent genetic anticipation does not appear to involve trinucleotide repeat expansion.

Adolescent↗
PubMed2002

The hormone-sensitive lipase i6 gene polymorphism and body fat accumulation.

BACKGROUND: The hormone sensitive lipase (HSL) catalyses the breakdown of adipose tissue triglycerides into free fatty acids. The objective of this study was to determine whether HSLi6 microsatellite allele 5 (A5) and/or homozygosity for this allele is associated with body fat in Swedes. DESIGN: A large case-control study on gender-specific association for several body fat-related clinical parameters to HSLi6 A5, and to HSLi6 A5 homozygosity, comparing A5 with the other alleles in group. The subjects were 323 obese patients (85 males, 238 females) without other metabolic complication, and 301 nonobese healthy individuals (134 males, 167 females). They were analyzed for various body fat-related clinical parameters, and HSLi6 genotype. RESULTS: Homozygosity for HSLi6 A5 was a risk factor for obesity, BMI > or = 30 kg m-2 (Odds ratio = 1.75, 95% CI 1.58-1.93) and body fat mass > 39.6% (Odds ratio = 1.89, 95% CI 1.60-2.23) in women. This genotype was also associated with increased diastolic blood pressure and triglyceride level among nonobese women, and with increased body fat mass and waist/hip ratio among nonobese men. CONCLUSION: HSLi6 A5 homozygosity is a risk factor for body fat accumulation.

Adult↗
PubMed2002

Physical map of the chromosome 6q22 region containing the oculodentodigital dysplasia locus: analysis of thirteen candidate genes and identification of novel ESTs and DNA polymorphisms.

Oculodentodigital dysplasia (ODDD) is an autosomal dominant condition with congenital anomalies of the craniofacial and limb regions and neurodegeneration. Genetic anticipation for the dysmorphic and neurologic features has been inferred in a few families. Our previous linkage studies have refined the ODDD candidate region to chromosome 6q22-->q23. In an attempt to clone the ODDD gene, we created a yeast artificial chromosome contig with 31 redundant clones spanning the region and identified and ordered candidate genes and markers. Fluorescent IN SITU hybridization mapped two of these YAC clones to chromosome 6q22.2 telomeric to a known 6q21 fragile site, excluding it as a possible cause of the suggested anticipation. We performed mutation analysis on thirteen candidate genes - GRIK2, HDAC2, COL10A1, PTD013, KPNA5, PIST, ROS1, BRD7, PLN, HSF2, PKIB, FABP7, and HEY2. Although no mutations were found, we identified 44 polymorphisms, including 28 single nucleotide polymorphisms. Direct cDNA selection was performed and fifty-five clones were found to contain sequences that were not previously reported as known genes or ESTs. These clones and polymorphisms will assist in the further characterization of this region and identification of disease genes.

Abnormalities, Multiple↗
PubMed2001

Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2.

The phenotypes in myotonic dystrophy types 1 and 2 (DM1 and DM2) are similar, suggesting a shared pathophysiologic mechanism. DM1 is caused by expansion of a CTG repeat in the DMPK gene. Pathogenic effects of this mutation are likely to be mediated, at least in part, by the expanded CUG repeat in mutant mRNA. The mutant transcripts are retained in the nucleus in multiple discrete foci. We investigated the possibility that DM2 is also caused by expansion of a CTG repeat or related sequence. Analysis of DNA by repeat expansion detection methods, and RNA by ribonuclease protection, did not show an expanded CTG or CUG repeat in DM2. However, hybridization of muscle sections with fluorescence-labeled CAG-repeat oligonucleotides showed nuclear foci in DM2 similar to those seen in DM1. Nuclear foci were present in all patients with symptomatic DM1 (n = 9) or DM2 (n = 9) but not in any disease controls or healthy subjects (n = 23). The foci were not seen with CUG- or GUC-repeat probes. Foci in DM2 were distinguished from DM1 by lower stability of the probe-target duplex, suggesting that a sequence related to the DM1 CUG expansion accumulates in the DM2 nucleus. Muscleblind proteins, which interact with expanded CUG repeats in vitro, localized to the nuclear foci in both DM1 and DM2. These results support the idea that nuclear accumulation of mutant RNA is pathogenic in DM1, suggest that a similar disease process occurs in DM2, and point to a role for muscleblind in the pathogenesis of both disorders.

Adult↗
PubMed2001

Altered dopaminergic transmission in the anorexic anx/anx mouse striatum.

We demonstrate abnormal dopaminergic neurotransmission in anorexic mice, homozygous for a recessive mutation (anx) causing starvation and motor disturbances. Isolated neurons from anx/anx striatum displayed a markedly increased activity of the Na+,K+-ATPase compared with normal littermates. Dopamine down-regulates Na+,K+-ATPase activity in striatal medium spiny neurons in rat, mouse and guinea pig. However, addition of dopamine in vitro failed to suppress the increased activity in anx/anx striatal neurons. Striatal dopamine and its metabolites, but not norepinephrine, were slightly but significantly lower in anx/anx mice than in normal littermates. We suggest that abnormal dopaminergic transmission may contribute to the anx phenotype.

Animals↗
PubMed2001

Expression of alpha-synuclein in the human brain: relation to Lewy body disease.

Alpha-synuclein is mutated in some hereditary cases of Parkinson's disease and the protein precipitates in Lewy bodies, the pathological hallmark of both Parkinson's disease and Lewy body disease. Transgenic mice overexpressing human wild-type alpha-synuclein develop alpha-synuclein-immunoreactive inclusions in brain regions typically affected with Lewy body disease. We used in situ hybridization to characterize alpha-synuclein expression and examine mRNA levels in patients affected with Lewy body disease and controls. Substantia nigra was avoided because of the extensive neuronal loss and cingulate gyrus was chosen as it is one of the diagnostic regions in Lewy body disease where Lewy bodies most frequently are demonstrated. beta-tubulin was used to control for neuronal degeneration. The alpha-synuclein probe showed intense labeling of pyramidal cells in lamina III and V in both patients and controls. We found no difference in alpha-synuclein mRNA levels and beta-tubulin mRNA was not significantly altered (P=0.06) in patient brains. There was no difference in the ratio of alpha-synuclein and beta-tubulin mRNA levels between patients and controls. Further, we found no relationship between alpha-synuclein mRNA levels and Lewy bodies. Great variability in alpha-synuclein mRNA levels among patients indicates that Lewy body disease may be a heterogeneous disorder with regard to alpha-synuclein involvement.

Aged↗
PubMed2001

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade enhances incidence and severity of experimental autoimmune neuritis in resistant mice.

Experimental autoimmune neuritis (EAN), an autoimmune inflammatory demyelinating disease of the peripheral nervous system, represents an animal model of the human Guillain-Barré syndrome. EAN can be induced by active immunization in several animals, including Lewis rats. In contrast, most strains of mice including the widely used C57BL/6 (B6) strain are reputedly resistant to the induction of EAN. In the present study, we demonstrate that in B6 mice, anti-CTLA-4 monoclonal antibody administration in conjunction with immunization with the P0 protein derived peptide 180-199 can induce clinical and pathological definite EAN. Upregulating effects of CTLA-4 blockade on initial and ongoing EAN are demonstrated. CTLA-4 blockade augmented cellular infiltration and enhanced demyelination in the target organ sciatic nerves as well as increased T cell proliferation in lymph node cells. Moreover, serum levels of IFN-gamma and IL-4 were increased. Thus, manipulation of CTLA-4/B7 costimulatory pathway by CTLA-4 blockade can promote autoreactivity and break the relative tolerance to peripheral autoantigen P0 in resistant B6 mice.

Abatacept↗
PubMed2001

Seasonal affective disorder and serotonin-related polymorphisms.

Disturbances in central serotonergic systems have been hypothesized to be involved in seasonal affective disorder (SAD). Association between SAD and the shorter allele of the serotonin transporter promoter repeat length polymorphism (5-HTTLPR) has been reported in an American sample. We have genotyped 82 SAD patients and 82 healthy controls from Sweden, Finland, and Germany for this and five other polymorphisms in the genes coding for serotonin receptors 5-HT2A and 5-HT2C, tryptophan hydroxylase and white. No associations with SAD or seasonality (seasonal variations in mood and behavior) were detected. Although minor effects cannot be excluded, our results suggest that these polymorphisms do not play a major role in the pathogenesis of SAD in the northern European population.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2001

Genetics of affective disorders.

Despite substantial evidence for heritability in affective disorders the contributing genes have proven elusive. Here we discuss the genetic epidemiology of depression, as well as methodological issues and results from molecular genetic studies. There has been rapid advances in genetics, genomics and statistical modelling, facilitating the search for molecular mechanisms underlying affective disorders and several strategies reviewed in this paper hold promise to provide progress in the field. Considering the poorly understood biological basis of vulnerability to affective disorders, the identification of genes involved in the pathophysiology will unravel mechanisms and pathways that could permit more personalized therapeutic strategies and result in new targets for pharmacological intervention.

Animals↗
PubMed2001

Insulin-like growth factor-II in endocrine pancreatic tumours. Immunohistochemical, biochemical and in situ hybridization findings.

In earlier studies a high-molecular-weight (HMW) insulin-like growth factor-II (IGF-II) peptide was identified in adult human pancreas and localized to the insulin-producing B-cells. This peptide has now been investigated in neoplastic insulin cells. Forty endocrine pancreatic tumours and 17 pancreatic adenocarcinomas of ductal type were included in the study. All cases were investigated with immunohistochemical techniques using antibodies to IGF-II, insulin, pro-insulin, glucagon, somatostatin, pancreatic polypeptide, gastrin and vasoactive intestinal peptide (VIP). Frozen tissue from nine tumours and two normal pancreatic glands was extracted, gel separated, and quantified using radioimmunoassay. The tumours were also investigated by in situ hybridization. IGF-II-immunoreactive cells were found in nearly all the 18 insulin-producing tumours (16/18), in a minority of the other endocrine tumours, but not in pancreatic adenocarcinomas. All extracts from the endocrine tumours showed varying amounts of IGF-II and had different molecular-weight forms. The immunohistochemical and radioimmunoassay findings are both based on immunological binding and were further confirmed by Northern blot and in situ hybridization. These results show that IGF-II is expressed in insulin-producing tumours as well as in pancreatic tumours producing other peptides, in contrast to normal pancreatic islets where IGF-II is found exclusively in insulin-producing cells.

Adolescent↗
PubMed2001

The effect of the beta(2) adrenoceptor gene Thr164Ile polymorphism on human adipose tissue lipolytic function.

A rare beta(2)-adrenoceptor gene polymorphism, Thr164Ile, has been described that impairs receptor function when transfected into cell lines. We investigated whether the polymorphism influences native receptor function by studying lipolysis in freshly isolated subcutaneous fat cells from 236 apparently healthy subjects. Twelve subjects were heterozygous for the 164Ile variant. The fat cells of Ile carriers displayed a 6 fold increase (P=0.02) in the lipolytic EC(50) of terbutaline (a selective beta(2)-adrenoceptor agonist), but no change in the lipolytic action of dobutamine (a selective beta(1)-adrenoceptor agonist), compared with the Thr carriers. Maximum adrenoceptor agonist stimulated lipolysis did not differ between Thr and Ile carriers. The influence of two other polymorphisms (Arg16Gly and Gln27Glu) in the beta(2)-adrenoceptor gene was considered. Six 164Ile carriers also carried the 16Gly and 27Glu alleles. The latter combination occurred among 105 of the 164Thr carriers. For the 16Gly27Glu subgroup, the EC(50) of terbutaline was about 10 fold higher in 164Ile as than in 164Thr carriers (P=0.02) but there was no difference between genotypes in maximum terbutaline action. There was no difference between groups in dobutamine action. In conclusion, the 164Ile variant of the beta(2)-adrenoceptor is associated with a decreased native adipocyte receptor function, as evidenced by a marked increase in the half maximal effective concentration of the lipolytic action of a selective beta(2)-adrenoceptor agonist. This suggests that genetic variance in the beta(2)-adrenoceptor gene might be important for catecholamine function in humans, at least as far as adipocyte lipolysis is concerned.

Adipose Tissue↗
PubMed2001

Androgen receptor trinucleotide repeat polymorphism and personality traits.

Human family and twin studies have established considerable heritable components influencing individual differences in personality traits as assessed by self-report questionnaires. We have investigated a trinucleotide repeat polymorphism in the androgen receptor gene and personality traits. Healthy Swedish subjects (n = 335) were assessed with the Karolinska Scales of Personality inventory. There were tendencies (P > or = 0.006) in some scales indicating possible relationships between the androgen receptor allele length and personality traits related to dominance and aggression. However, after correction for multiple testing, no significant differences were found. We conclude that no significant association could be found between the androgen receptor polymorphism investigated and any personality trait, although the tendencies found are worthwhile subjects for replication attempts.

Adult↗
PubMed2001

Genetic survival analysis of age-at-onset of bipolar disorder: evidence for anticipation or cohort effect in families.

Age-at-onset (AAO) in a number of extended families ascertained for bipolar disorder was analysed using survival analysis techniques, fitting proportional hazards models to estimate the fixed effects of sex, year of birth, and generation, and a random polygenic genetic effect. Data comprised the AAO (for 171 affecteds) or age when last seen (ALS) for 327 unaffecteds, on 498 individuals in 27 families. ALS was treated as the censored time in the statistical analyses. The majority of individuals classified as affected were diagnosed with bipolar I and II (n = 103) or recurrent major depressive disorder (n = 68). In addition to the significant effects of sex and year of birth, a fitted 'generation' effect was highly significant, which could be interpreted as evidence for an anticipation effect. The risk of developing bipolar or unipolar disorder increased twofold with each generation descended from the oldest founder. However, although information from both affected and unaffected individuals was used to estimate the relative risk of subsequent generations, it is possible that the results are biased because of the 'Penrose effect'. Females had a twofold increased risk in developing depressive disorder relative to males. The risk of developing bipolar or unipolar disorder increased by approximately 4% per year of birth. A polygenic component of variance was estimated, resulting in a 'heritability' of AAO of approximately 0.52. In a family showing strong evidence of linkage to chromosome 4p (family 22), the 'affected haplotype' increased the relative risk of being affected by a factor of 46. In this family, there was strong evidence of a time trend in the AAO. When either year of birth or generation was fitted in the model, these effects were highly significant, but neither was significant in the presence of the other. For this family, there was no increase in trinucleotide repeats measured by the repeat expansion detection method in affected individuals compared with control subjects. Proportional hazard models appear appropriate to analyse AAO data, and the methodology will be extended to map quantitative trait loci (QTL) for AAO.

Adult↗
PubMed2001

A common hormone-sensitive lipase i6 gene polymorphism is associated with decreased human adipocyte lipolytic function.

Hereditary factors may be involved in the pathogenesis of type 2 diabetes. A polymorphism in the hormone-sensitive lipase (HSL) gene (HSLi6) is associated with obesity and diabetes, although it is unknown whether the polymorphism is functional and thereby influences lipolysis. We genotyped 355 apparently healthy nonobese male and female subjects for the HSLi6 polymorphism. Allele 5 was found to be the most common allele (allele frequency 0.57). In 117 of the subjects, we measured abdominal subcutaneous fat cell lipolysis induced by drugs acting at various steps in the lipolytic cascade. The lipolysis rate induced by norepinephrine isoprenaline (acting on beta-adrenoceptors), forskolin (acting on adenylyl cyclase), and dibutyryl cyclic AMP (acting on HSL) were all decreased by approximately 50% in allele 5 homozygotes, as compared with noncarriers. Heterozygotes showed an intermediate lipolytic rate. The difference in lipolysis rate between genotypes was more pronounced in men than in women. We conclude that allele 5 of the HSLi6 polymorphism is associated with a marked decrease in the lipolytic rate of abdominal fat cells. This may in turn contribute to the development of obesity.

Abdomen↗
PubMed2001

Dominantly inherited familial myasthenia gravis as a separate genetic entity without involvement of defined candidate gene loci.

Myasthenia gravis (MG) is a sporadic autoimmune disorder affecting neuromuscular transmission. Very rarely autoimmune myasthenia gravis may be inherited within a family. We present here the genetic analysis of a Hungarian family where nine members from two generations are affected by myasthenia gravis. Genetic characterisation of this unique Hungarian family using linkage analysis and mutation screening excludes the involvement of defined candidate gene loci. These findings point to familial MG as a separate genetic entity. Identification of the underlying genetic defect in this family may greatly enhance our understanding of the pathogenesis of myasthenia gravis.

Adolescent↗