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Jurgen Del-Favero

Publications and source records attributed to Jurgen Del-Favero.

At least 19 recordsLinked to original sources
PubMed2006

APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy.

We assessed the impact of amyloid precursor protein (APP) gene locus duplications in early onset Alzheimer's disease in a Dutch population-based sample. Using real-time PCR and an in-house-developed multiplex amplicon quantification assay, we identified a genomic APP duplication in 1 out of 10 multigenerational families segregating early onset Alzheimer's disease. In this family, cerebral amyloid angiopathy (CAA) coincided with this disease. The duplicated genomic region included no other genes than APP and extended maximally over 0.7 Mb. In a sample of 65 familial early onset patients, we observed the same APP genomic duplication in one patient (1.7%), while in 36 isolated patients duplications in the APP locus were absent. This indicated that APP locus duplications explained <2% of familial, non-autosomal dominant Alzheimer's disease and are an infrequent cause of de novo mutation. Our findings corroborated a recent French study, and indicated that investigating genomic duplications in the APP locus in families segregating Alzheimer's disease and CAA should be considered.

Adult↗
PubMed2006

Expression profiling of endocrine-disrupting compounds using a customized Cyprinus carpio cDNA microarray.

Exposure to a variety of anthropogenic compounds has been shown to interfere with normal development, physiology, and reproduction in a wide range of organisms, both in laboratory studies and wildlife. We have developed a Cyprinus carpio cDNA microarray consisting of endocrine-related genes. In the current study, we investigated the applicability of this microarray (1) to study the molecular effects induced by exposure to a variety of endocrine-disrupting compounds (EDCs) in fish and (2) to discriminate the specific transcriptional profiles associated with these compounds. To that purpose, gene expression profiles were generated in livers of juvenile carp exposed to 14 Organization of Economical Cooperation Development (OECD)-recommended reference EDCs (17beta-estradiol, 17alpha-ethinylestradiol, 4-nonylphenol, bisphenol A, tamoxifen, 17alpha-methyltestosterone, 11-ketotestosterone, dibutyl phthalate, flutamide, vinclozolin, hydrocortisone, CuCl(2), propylthiouracil, and a mixture of L-triiodothyronine and L-thyroxine). Our results show that, in addition to some expression similarities between analogous acting substances, each individual compound produced its own unique expression pattern on the array, distinct from the profiles generated by the other compounds. In addition, we were able to identify a minimal subset of genes, which also allowed to discriminate between the different compounds. Overall, our findings suggest that the developed cDNA array has great promise to screen new and existing chemicals on their endocrine-disruptive potential and to identify distinct classes of EDCs.

Animals↗
PubMed2006

Association of brain-specific tryptophan hydroxylase, TPH2, with unipolar and bipolar disorder in a Northern Swedish, isolated population.

CONTEXT: Tryptophan hydroxylase is the rate-limiting enzyme in the serotonin (5-HT) biosynthetic pathway responsible for the regulation of serotonin levels. Tryptophan hydroxylase 2 (TPH2) was found to be solely expressed in the brain and therefore considered an important susceptibility gene in psychiatric disorders. OBJECTIVE: To determine the role of the brain-specific TPH2 gene in unipolar (UP) disorder and bipolar (BP) disorder in a northern Swedish, isolated population. DESIGN: HapMap-based haplotype-tagging single nucleotide polymorphism (htSNP) patient-control association study. SETTING: A northern Swedish, isolated population. PARTICIPANTS: One hundred thirty-five unrelated patients with UP disorder, 182 unrelated patients with BP disorder, and 364 unrelated control individuals. RESULTS: Significant allelic association was identified in our UP disorder association sample for an htSNP located in the 5' promoter region (rs11178997; P = .001). Haplotype analysis supported this significant result by the presence of a protective factor on hapblock 2 (P(specific) = .002). In the BP disorder association sample, single-marker association identified a significant htSNP in the upstream regulatory region (rs4131348; P = .004). Moreover, haplotype analysis in the BP disorder sample showed that the same htSNPs from hapblock 2 associated with UP disorder were also significantly associated with BP disorder (P(specific) = .002). CONCLUSIONS: Haplotype-based analysis of TPH2 in patients with UP and BP disorder and controls from northern Swedish descent provides preliminary evidence for protective association in both disorders and thus supports a central role for TPH2 in the pathogenesis of affective disorders.

Aged↗
PubMed2006

Microdeletions involving the SCN1A gene may be common in SCN1A-mutation-negative SMEI patients.

Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome is a rare epilepsy syndrome. In 30 to 70% of SMEI patients, truncating and missense mutations in the neuronal voltage-gated sodium-channel alpha-subunit gene (SCN1A) have been identified. The majority of patients have truncating mutations that are predicted to be loss-of-function alleles. Because mutation detection studies use PCR-based sequencing or conformation sensitive gel electrophoresis (CSGE), microdeletions, which are also predicted to be loss-of-function alleles, can easily escape detection. We selected 11 SMEI patients with or without additional features who had no SCN1A mutation detectable with sequencing analysis. In addition, none of the patients was heterozygous for any of the SNPs in SCN1A, indicating that they were either homozygous for all SNPs or hemizygous due to a microdeletion of the gene. We subsequently analyzed these patients for the presence of microdeletions in SCN1A using a quantitative PCR method named multiplex amplicon quantification (MAQ), and observed three patients missing one copy of the SCN1A gene. All three microdeletions were confirmed by fluorescence in situ hybridization (FISH). These findings demonstrate that a substantial percentage of SCN1A-mutation-negative SMEI patients with or without additional features carry a chromosomal microdeletion comprising the SCN1A gene and that haploinsufficiency of the SCN1A gene is a cause of SMEI.

Child↗
PubMed2006

Major affective disorders and schizophrenia: a common molecular signature?

Psychiatric disorders, including affective disorders (AD) and schizophrenia (SZ) are among the most common disabling brain diseases in Western populations and result in high costs in terms of morbidity as well as mortality. Although their etiology and pathophysiology is largely unknown, family-, twin-, and adoption studies argue for a strong genetic determination of these disorders. These studies indicate that there is between 40 and 85% heritability for these disorders but point also to the importance of environmental factors. Therefore, any research strategy aiming at the identification of genes involved in the development of AD and SZ should account for the complex nature (multifactorial) of these disorders. During the last decade, molecular genetic studies have contributed a great deal to the identification of genetic factors involved in complex disorders. Here we provide a comprehensive review of the most promising genes for AD and SZ, and the methods and approaches that were used for their identification. Also, we discuss the current knowledge and hypotheses that have been formulated regarding the effect of variations on protein functioning as well as recent observations that point to common molecular mechanisms.

Dopamine↗
PubMed2006

Glucocorticoid receptor gene-based SNP analysis in patients with recurrent major depression.

Dysregulation of the hypothalamic-pituitary-adrenal axis, one of the stress-response systems, is one of the key neurobiological features of major depression (MDD). Data supporting the notion that glucocorticoid-mediated feedback inhibition is impaired in MDD come from a multitude of studies demonstrating nonsuppression of cortisol secretion following administration of the synthetic glucocorticoid dexamethasone. We examined whether genetic variations in the glucocorticoid receptor gene (Nuclear Receptor Subfamily 3, Group C, Member 1; NR3C1) could be associated with increased susceptibility for MDD using a whole gene-based association analysis of single nucleotide polymorphisms (SNPs). Four SNPs were identified in NR3C1 and genotyped in two well-diagnosed samples of patients with MDD ascertained in Belgium and northern Sweden, and matched control samples. In total, 314 MDD patients and 354 control individuals were included in the study. In the Belgian sample, we observed significant allele (p=0.02) and genotype (p=0.02) association with an SNP in the promoter region (NR3C1-1); in the Swedish sample, we observed significant allele (p=0.02) and genotype (p=0.02) association with the R23K SNP. The haplotype association studies showed modest evidence for an involvement of the 5' region of the NR3C1 gene in the genetic vulnerability for MDD. This study suggests that polymorphisms in the 5' region of the NR3C1 gene may play a role in the genetic vulnerability for MDD.

Belgium↗
PubMed2006

Lack of genetic association between the phospholipase A2 gene and bipolar mood disorder in a European multicentre case-control study.

The possible association between phospholipase A2 gene and bipolar mood disorder was examined in 557 bipolar patients and 725 controls (all personally interviewed), recruited from seven countries (Belgium, Bulgaria, Croatia, Germany, Greece, Italy, and UK). The frequencies of the eight alleles that were identified did not differ between patients and control individuals in the whole population, while the power to detect an association based on our sample was relatively high. Some differences were noted among the various ethnic groups, but no significant trends existed, suggesting that population stratification by country may not be responsible for a type II error. On the basis of these results, mutations of the phospholipase A2 gene, at least in the region close to the polymorphism examined between exons 1 and 2, are not involved in the pathogenesis of bipolar mood disorder.

Base Pairing↗
PubMed2006

No allelic association or interaction of three known functional polymorphisms with bipolar disorder in a northern Swedish isolated population.

Most genetic association studies in bipolar disorder have focussed on genes involved in major neurotransmitter systems or brain development. Functional polymorphisms in the serotonin transporter (5-HTTLPR), catechol-O-methyltransferase (Val158Met) and dopamine D3 receptor (Ser9Gly) genes have all been associated with bipolar disorder. We aimed at investigating whether these functional variants contribute to the genetic etiology of bipolar disorder in a northern Swedish isolated population. Moreover, we wanted to gain information about the synergistic contribution of these functional variants. Neither of these functional polymorphisms was associated with bipolar disorder in the northern Swedish patient-control sample nor did we find evidence of gene-gene interaction. Together, our data suggest that these functional variants are not involved in the etiology of bipolar disorder in the northern Swedish population nor did gene-gene interaction analysis support a central role of these variants in bipolar disorder.

Adult↗
PubMed2006

Lack of association of an insertion/deletion polymorphism in the G protein-coupled receptor 50 with bipolar disorder in a Northern Swedish population.

GPR50 is a G protein-coupled receptor, located on Xq28 and related to the melatonin receptor family. It is suggested as a functional and positional candidate gene for bipolar disorder (BP). Recently an insertion/deletion polymorphism in GPR50, Delta502-505, was found to be associated with BP in a Scottish association sample (P=0.007). When the analysis was restricted to female subjects, the association increased in significance (P=0.00023). We attempted to replicate this finding in a Northern Swedish association sample, but no significant association was detected (P=0.7, women only: P=0.65).

Bipolar Disorder↗
PubMed2005

Genome-wide linkage of febrile seizures and epilepsy to the FEB4 locus at 5q14.3-q23.1 and no MASS1 mutation.

Febrile seizures (FS) represent the most common seizure disorder in childhood and contribution of a genetic predisposition has been clearly proven. In some families FS is associated with a wide variety of afebrile seizures. Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with a spectrum of phenotypes including FS, atypical febrile seizures (FS+) and afebrile generalized and partial seizures. Mutations in the genes SCN1B, SCN1A and GABRG2 were identified in GEFS+ families. GEFS+ is genetically heterogeneous and mutations in these three genes were detected in only a minority of the families. We performed a 10 cM density genome-wide scan in a multigenerational family with febrile seizures and epilepsy and obtained a maximal multipoint LOD score of 3.12 with markers on chromosome 5q14.3-q23.1. Fine mapping and segregation analysis defined a genetic interval of approximately 33 cM between D5S2103 and D5S1975. This candidate region overlapped with a previously reported locus for febrile seizures (FEB4) in the Japanese population, in which MASS1 was proposed as disease gene. Mutation analysis of the exons and exon-intron boundaries of MASS1 in our family did not reveal a disease causing mutation. Our linkage data confirm for the first time that a locus on chromosome 5q14-q23 plays a role in idiopathic epilepsies. However, our mutation data is negative and do not support a role for MASS1 suggesting that another gene within or near the FEB4 locus might exist.

Adolescent↗
PubMed2005

High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy.

Two extended haplotypes exist across the tau gene-H1 and H2-with H1 consistently associated with increased risk of progressive supranuclear palsy (PSP). Using 15 haplotype tagging SNPs (htSNPs), capturing >95% of MAPT haplotype diversity, we performed association analysis in a US sample of 274 predominantly pathologically confirmed PSP patients and 424 matched control individuals. We found that PSP risk is associated with one of two major ancestral H1 haplotypes, H1B, increasing from 14% in control individuals to 22% in PSP patients (P<0.001). In young PSP patients, the H1B risk could be localized to a 22 kb regulatory region in intron 0 (P<0.001) and could be fully explained by one SNP, htSNP167, creating a LBP-1c/LSF/CP2 site, shown to regulate the expression of genes in other neurodegenerative disorders. Luciferase reporter data indicated that the 182 bp conserved regulatory region, in which htSNP167 is located, is transcriptionally active with both alleles differentially influencing expression. Further, we replicated the htSNP167 association in a second, independently ascertained US PSP patient-control sample. However, the htSNP association showed that H1 risk alone could not explain the overall differences in H1 and H2 frequencies in PSP patients and control individuals. Thus, risk variants on different H1 htSNP haplotypes and protective variants on H2 contribute to population risk for PSP.

Age Factors↗
PubMed2005

Mutations in SEPT9 cause hereditary neuralgic amyotrophy.

Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant recurrent neuropathy affecting the brachial plexus. HNA is triggered by environmental factors such as infection or parturition. We report three mutations in the gene septin 9 (SEPT9) in six families with HNA linked to chromosome 17q25. HNA is the first monogenetic disease caused by mutations in a gene of the septin family. Septins are implicated in formation of the cytoskeleton, cell division and tumorigenesis.

Amino Acid Sequence↗
PubMed2005

Linkage and association studies identify a novel locus for Alzheimer disease at 7q36 in a Dutch population-based sample.

We obtained conclusive linkage of Alzheimer disease (AD) with a candidate region of 19.7 cM at 7q36 in an extended multiplex family, family 1270, ascertained in a population-based study of early-onset AD in the northern Netherlands. Single-nucleotide polymorphism and haplotype association analyses of a Dutch patient-control sample further supported the linkage at 7q36. In addition, we identified a shared haplotype at 7q36 between family 1270 and three of six multiplex AD-affected families from the same geographical region, which is indicative of a founder effect and defines a priority region of 9.3 cM. Mutation analysis of coding exons of 29 candidate genes identified one linked synonymous mutation, g.38030G-->C in exon 10, that affected codon 626 of the PAX transactivation domain interacting protein gene (PAXIP1). It remains to be determined whether PAXIP1 has a functional role in the expression of AD in family 1270 or whether another mutation at this locus explains the observed linkage and sharing. Together, our linkage data from the informative family 1270 and the association data in the population-based early-onset AD patient-control sample strongly support the identification of a novel AD locus at 7q36 and re-emphasize the genetic heterogeneity of AD.

Aged↗
PubMed2005

Patient-control association study of substance P-related genes in unipolar and bipolar affective disorders.

In the search of genes potentially implicated in the aetiology of affective disorders (AD), SUBSTANCE P (SP) pathway is receiving increased interest. SP receptor antagonists, such as MK-869 and L-759274, have been shown to have antidepressant effect. Results from preclinical and human studies implicate SP and its pathway in the pathophysiology of mood disorders. We investigated a possible association between 20 single nucleotide polymorphisms (SNPS) among four SP-related genes and unipolar and bipolar ad (UPAD and BPAD) in a first sample of 92 UPAD patients and 92 control individuals and in a replication sample of 92 UPAD patients and 92 control individuals. An additional sample of 113 BPAD patients has also been ascertained. Our results showed a significant association between the angiotensin-converting enzyme gene (ACE1) and UPAD in our first sample, but not in the replication sample. No significant evidence of association was found in other SP-related genes. We did not find any association in the BPAD sample. When pooling first and replication UPAD samples, an association was found between ACE1 and a subgroup of patients remaining depressed after an adequate antidepressant treatment. In conclusion, our findings do not support a major contribution of SP-related genes in UPAD and BPAD, but provides some evidence of an ace influence in treatment response to antidepressants.

Adult↗
PubMed2005

Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low-copy repeats in the tau region.

Familial frontotemporal dementia (FTD), characterized by tau-negative, ubiquitin-positive inclusions at autopsy, is linked to a chromosomal region at 17q21 (FTDU-17), encompassing the gene encoding the microtubule associated protein tau, MAPT. Mutations in MAPT were previously identified in familial FTD with parkinsonism (FTDP-17); however, in FTDU-17 patients, no pathogenic mutations were found in exonic regions consistent with the lack of tauopathy in FTDU-17 brains. Here, we excluded mutations in MAPT by genomic sequencing of 138.5 kb in FTDU-17 patients. Next, to facilitate the identification of the actual underlying genetic defect, we assembled the 6.5 Mb FTDU-17 sequence. Annotation demonstrated that MAPT is surrounded by three highly homologous low-copy repeats (LCRs) in a region of 1.7 Mb. Using evolutionary studies, short tandem repeat-based linkage disequilibrium (LD) and macro-restriction mapping, we demonstrated that these LCRs are at the basis of a series of rearrangements in the MAPT genomic region. One is an inversion that occurred 3 million years ago and resulted in a common polymorphism in humans to date. This inversion plus flanking LCRs spanned approximately 1.3 Mb and was shown to underlie the extended LD and haplotypes H1 and H2 across MAPT. However, in the FTDU-17 families, we ascertained segregation analysis precluding a relationship between the FTDU-17 and the H1/H2 inversion. The presence of multiple homologous LCRs in the region predicts that other potentially more complex genomic rearrangements might be underlying FTDU-17.

Chromosome Inversion↗
PubMed2005

No implication of brain-derived neurotrophic factor (BDNF) gene in unipolar affective disorder: evidence from Belgian first and replication patient-control studies.

Several lines of evidence have suggested an implication of brain-derived neurotrophic factor (BDNF) in unipolar affective disorder (UPAD). In the present study, we investigated the role of BDNF gene in UPAD in two independent samples of 92 patients/92 controls and 156 patients/197 controls. Two single nucleotide polymorphisms (SNPs) were investigated. We found no significant differences of BDNF gene SNPs distribution between UPAD patients and controls in both samples. Haplotype analyses were performed on both samples. A statistical difference was found between cases and controls in the first sample but not in the second. These results are not in favour of an implication of BDNF in UPAD but need to be replicated before final conclusion.

Adult↗