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Thomas Meitinger

Publications and source records attributed to Thomas Meitinger.

At least 19 recordsLinked to original sources
PubMed2026

Genetic screening of children for familial hypercholesterolaemia: the VRONI study.

BACKGROUND AND AIMS: The role of genetic testing as part of universal screening programmes for familial hypercholesterolaemia (FH) in children is not well defined. Here, a two-step approach to identify children carrying FH-causing variants was investigated. METHODS: In this study from Southern Germany, paediatricians were invited to offer FH screening to all children aged 4.8-14.9 years at routine paediatric examinations. The FH screening programme began in September 2020 in Bavaria and has involved up to 480 paediatricians. It included biochemical and genetic testing using 0.2 mL of blood taken from a fingertip. In case of low-density lipoprotein cholesterol (LDL-C) serum concentration ≥3.36 mmol/L (≥130 mg/dL), FH-causing variants were determined in the same sample with a focused panel covering most frequent variants (n = 48) and sequencing of relevant genes. RESULTS: Out of 25 431 children screened so far, 1689 children had an LDL-C ≥ 3.36 mmol/L (>130 mg/dL), which defined this concentration as the 93rd percentile. Pathogenic variants were identified by the focused panel in 157 and by next-generation sequencing in 283 children, respectively. While 17% (283/1670) of all genetically analysed children tested positive, the fraction of individuals with FH-causing variants increased across the spectrum of LDL-C serum concentrations from 4.7% (23/492) at 3.36-3.49 mmol/L (130-135 mg/dL) to 78.6% (81/103) above 5.17 mmol/L (200 mg/dL). Overall, the prevalence of FH-causing variants was high (1:90). One reason was a founder variant (n = 63) within the LDLR gene, found 40 times more frequent than European average. The analysis of recruitment data revealed significant ascertainment bias, with lower recruitment rate practices exhibiting higher prevalence. After adjustment for the bias using a generalized linear mixed model, the predicted prevalence was 1 in 163 (0.61%), which is highly consistent with large-scale genomic benchmarks as gnomAD (1:165, n = 622 057) and the UK Biobank (1:176, n = 48 741). CONCLUSIONS: The prevalence of FH determined in this study is significantly higher than previously published estimates (∼1:250), highlighting the importance of this condition for public health and supporting calls for a national paediatric screening programme, given the availability of effective treatment options. For children between 5 and 15 years, biochemical screening is an effective way to select patients for genetic testing, with sequencing of candidate genes being superior to variant screening. In summary, the VRONI study demonstrates the feasibility and efficacy of a combined biochemical and genetic screening for FH in children.

Humans↗
PubMed2006

Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis.

Leber congenital amaurosis (LCA) is one of the main causes of childhood blindness. To date, mutations in eight genes have been described, which together account for approximately 45% of LCA cases. We localized the genetic defect in a consanguineous LCA-affected family from Quebec and identified a splice defect in a gene encoding a centrosomal protein (CEP290). The defect is caused by an intronic mutation (c.2991+1655A-->G) that creates a strong splice-donor site and inserts a cryptic exon in the CEP290 messenger RNA. This mutation was detected in 16 (21%) of 76 unrelated patients with LCA, either homozygously or in combination with a second deleterious mutation on the other allele. CEP290 mutations therefore represent one of the most frequent causes of LCA identified so far.

Alleles↗
PubMed2006

A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization.

Extremes of the electrocardiographic QT interval, a measure of cardiac repolarization, are associated with increased cardiovascular mortality. We identified a common genetic variant influencing this quantitative trait through a genome-wide association study on 200 subjects at the extremes of a population-based QT interval distribution of 3,966 subjects from the KORA cohort in Germany, with follow-up screening of selected markers in the remainder of the cohort. We validated statistically significant findings in two independent samples of 2,646 subjects from Germany and 1,805 subjects from the US Framingham Heart Study. This genome-wide study identified NOS1AP (CAPON), a regulator of neuronal nitric oxide synthase, as a new target that modulates cardiac repolarization. Approximately 60% of subjects of European ancestry carry at least one minor allele of the NOS1AP genetic variant, which explains up to 1.5% of QT interval variation.

Adaptor Proteins, Signal Transducing↗
PubMed2006

A common genetic variant is associated with adult and childhood obesity.

Obesity is a heritable trait and a risk factor for many common diseases such as type 2 diabetes, heart disease, and hypertension. We used a dense whole-genome scan of DNA samples from the Framingham Heart Study participants to identify a common genetic variant near the INSIG2 gene associated with obesity. We have replicated the finding in four separate samples composed of individuals of Western European ancestry, African Americans, and children. The obesity-predisposing genotype is present in 10% of individuals. Our study suggests that common genetic polymorphisms are important determinants of obesity.

Adult↗
PubMed2006

Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative population-based sample and obese adults from Germany.

CONTEXT: Autosomal dominant inheritance of mutations in the melanocortin-4 receptor gene (MC4R) is currently regarded as the most relevant genetic cause for extreme obesity and affects 2-4% of extremely obese individuals. OBJECTIVE: Our objective was to assess the relevance of MC4R mutations in a German population-based sample. DESIGN AND SETTING: We conducted a mutation screen of the MC4R gene by capillary electrophoresis-based single-strand conformation polymorphism analysis and denaturing HPLC. PARTICIPANTS: Subjects included 4068 individuals of a German population-based study group [Kooperative Gesundheitsforschung im Raum Augsburg, Survey 4 (KORA-S4); i.e. Cooperative Health Research in the Region of Augsburg] and 1003 German obese adults (body mass index >or= 30 kg/m(2)). MAIN OUTCOME MEASURES: Samples with aberrant capillary electrophoresis-based single-strand conformation polymorphism analysis/denaturing HPLC patterns were resequenced. Functional studies including agonistic receptor stimulation (Nle-D-Phe-alpha-, alpha-, and beta-MSH) and cell surface expression assays were performed. RESULTS: Sixteen (six novel) coding nonsynonymous mutations were detected in 27 heterozygous individuals of KORA-S4. Four of the mutation alleles led to impaired receptor function in vitro; however, none of these six heterozygous mutation carriers was obese (body mass index >or= 30 kg/m(2)). In the obese adults, six coding nonsynonymous and a nonsense mutation were detected in 13 individuals. Only the nonsense mutation allele entailed impaired receptor function. CONCLUSIONS: Our study depicts prevalence, spectrum, and functional characterization of MC4R mutations in the German population-based sample KORA-S4. In this epidemiological study group, individuals heterozygous for nonsynonymous MC4R mutation alleles entailing impaired function were not obese. Furthermore, nonsynonymous MC4R mutations causing impaired receptor function were rare in German obese adults (two in 1003 = 0.2%).

Adult↗
PubMed2006

Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation.

OBJECTIVE: Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterized by magnetic resonance imaging (MRI) changes in basal ganglia. Both missense and nonsense mutations have been found in such patients in a gene encoding the mitochondrial pantothenate kinase (PANK2). METHODS: We completed a mutation screen in 72 patients with the diagnosis NBIA based on clinical findings and radiological imaging. The entire coding region of the PANK2 gene (20p12.3) was investigated for point mutations and deletions. RESULTS: We uncovered both mutant alleles in 48 patients. Deletions accounted for 4% of mutated alleles. Patients with two loss-of-function alleles (n = 11) displayed symptoms always at an early stage of life. In the presence of missense mutations (n = 37), the age of onset correlated with residual activity of the pantothenate kinase. Progression of disease measured by loss of ambulation was variable in both groups. We did not observe a strict correlation between the eye-of-the-tiger sign and PANK2 mutations. In 24 patients, no PANK2 mutation was identified. INTERPRETATION: Deletion screening of PANK2 should be part of the diagnostic spectrum. Factors other than enzymatic residual activity are determining the course of disease. There are strong arguments in favor of locus heterogeneity.

Adolescent↗
PubMed2006

Evidence for further genetic locus heterogeneity and confirmation of RLS-1 in restless legs syndrome.

Restless legs syndrome (RLS; MIM 102300) is a common neurological disorder characterized by dysesthesias and an urge to move the lower limbs. The symptoms predominantly occur at rest, in the evening, and improve with movement. There is a high familial aggregation but gene mutations have not yet been found. Three loci for RLS on chromosomes 12q, 14q, and 9p (RLS-1, RLS-2, and RLS-3) have been reported with a recessive (RLS-1) and autosomal dominant (RLS-2, RLS-3) mode of inheritance, respectively. The overall contribution of these loci to this disorder is not known. To evaluate the significance of these loci, we investigated 12 RLS families for possible linkage to these chromosomal regions. Genotyping was carried out in 70 affected family members using 26 polymorphic microsatellite markers (chromosome 12: 7; chromosome 14: 7, chromosome 9: 12). Linkage analysis was carried out using the published parameters applied in the original studies (chromosome 12: q=0.25, f0=0.005, f1=0.005, f2=0.8; chromosome 14: q=0.003, f0=0.005, f1=f2=0.95; chromosome 9: q=0.001, f0=0.005, f1=f2=0.95; affected individuals only). In addition, transmission disequilibrium test (TDT) analyses were done. We found evidence for linkage on chromosome 12 using the TDT. Linkage to RLS-2 and RLS-3 was excluded in 1 of 12 families. This supports the existence of RLS-1 and provides evidence for the likelihood of further genetic locus heterogeneity of RLS. Investigations in additional RLS families are required to confirm the known loci and further genome wide linkage analyses have the potential to identify additional RLS loci.

Adolescent↗
PubMed2006

Restless legs syndrome: epidemiological and clinicogenetic study in a South Tyrolean population isolate.

Genetic contributions to restless legs syndrome (RLS) have been consistently recognized from population and family studies. To determine the clinical and genetic features of RLS in a population isolate and explore linkage to three previously described susceptibility loci on chromosomes 12q, 14q, and 9p, respectively, an isolated population in the South Tyrolean Alps was identified and 530 adults participated in the study. Using a two-step strategy, 47 patients with idiopathic RLS were ascertained. The prevalence in the population was 8.9%. Twenty-eight patients (59.6%) had at least one affected first-degree relative and were classified as hereditary cases. In a single extended pedigree, linkage to known RLS loci was investigated specifying autosomal dominant and recessive models; parametric and nonparametric multipoint linkage scores were computed. None of the calculated linkage scores was suggestive of linkage between RLS and any of the three investigated loci. This study was conducted in a population isolate providing for a homogeneous genetic and environmental background. The absence of a suggestive linkage signal at the three known RLS susceptibility loci is indicative of further locus heterogeneity of this frequent disorder and encourages further studies to unveil the genetic causes of RLS.

Adult↗
PubMed2006

Proteome analysis of mitochondrial outer membrane from Neurospora crassa.

The mitochondrial outer membrane mediates numerous interactions between the metabolic and genetic systems of mitochondria and the rest of the eukaryotic cell. We performed a proteomic study to discover novel functions of components of the mitochondrial outer membrane. Proteins of highly pure outer membrane vesicles (OMV) from Neurospora crassa were identified by a combination of LC-MS/MS of tryptic peptide digests and gel electrophoresis of solubilized OMV proteins, followed by their identification using MALDI-MS PMF. Among the 30 proteins found in at least three of four separate analyses were 23 proteins with known functions in the outer membrane. These included components of the import machinery (the TOM and TOB complexes), a pore-forming component (porin), and proteins that control fusion and fission of the organelle. In addition, proteins playing a role in various biosynthetic pathways, whose intracellular location had not been established previously, could be localized to the mitochondrial outer membrane. Thus, the proteome of the outer membrane can help in identifying new mitochondria-related functions.

DNA, Recombinant↗
PubMed2005

The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity.

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been recently identified in families with autosomal dominant late-onset Parkinson disease (PD). The LRRK2 protein consists of multiple domains and belongs to the Roco family, a novel group of the Ras/GTPase superfamily. Besides the GTPase (Roc) domain, it contains a predicted kinase domain, with homology to MAP kinase kinase kinases. Using cell fractionation and immunofluorescence microscopy, we show that LRRK2 is localized in the cytoplasm and is associated with cellular membrane structures. The purified LRRK2 protein demonstrates autokinase activity. The disease-associated I2020T mutant shows a significant increase in autophosphorylation of approximately 40% in comparison to wild-type protein in vitro. This suggests that the pathology of PD caused by the I2020T mutation is associated with an increase rather than a loss in LRRK2 kinase activity.

Blotting, Western↗
PubMed2005

Systematic mutation analysis of KIAA0767 and KIAA1646 in chromosome 22q-linked periodic catatonia.

BACKGROUND: Periodic catatonia is a familial subtype of schizophrenia characterized by hyperkinetic and akinetic episodes, followed by a catatonic residual syndrome. The phenotype has been evaluated in two independent genome-wide linkage scans with evidence for a major locus on chromosome 15q15, and a second independent locus on chromosome 22qtel. METHODS: In the positional and brain-expressed candidate genes KIAA0767 and KIAA1646, we searched for variants in the complete exons and adjacent splice-junctions as well as in parts of the 5'- and 3'-untranslated regions by means of a systematic mutation screening in individuals from chromosome 22q-linked pedigrees. RESULTS: The mutation scan revealed 24 single nucleotide polymorphisms, among them two rare codon variants (KIAA0767: S159I; KIAA1646: V338G). However, both were neither found segregating with the disease in the respective pedigree nor found at a significant frequency in a case-control association sample. CONCLUSION: Starting from linkage signals at chromosome22qtel in periodic catatonia, we screened two positional brain-expressed candidate genes for genetic variation. Our study excludes genetic variations in the coding and putative promoter regions of KIAA0767 and KIAA1646 as causative factors for periodic catatonia.

Case-Control Studies↗
PubMed2005

Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk.

Age-related macular degeneration (AMD) is a multifactorial disease and a prevalent cause of visual impairment in developed countries. Risk factors include environmental components and genetic determinants. The complement factor H (CFH) has been the first major susceptibility gene for AMD identified within 1q32. Here, we focused on a second region of interest in 10q26 where a recent meta-analysis revealed strongest evidence for linkage to AMD at a genome-wide significance level. Within an interval of 22 Mb, we have analyzed 93 single nucleotide polymorphisms for allelic association with AMD in two independent case-control cohorts of German origin (AMD(combined) n=1166; controls(combined) n=945). Significant association was found across a 60 kb region of high linkage disequilibrium harboring two genes PLEKHA1 and hypothetical LOC387715. The strongest association (P=10(-34)) centered over a frequent coding polymorphism, Ala69Ser, at LOC387715, strongly implicating this gene in the pathogenesis of AMD. Besides abundant expression in placenta, we demonstrate weak expression of LOC387715 in the human retina. At present, however, there is no functional information on this gene, which appears to have evolved recently within the primate lineage. The joint contribution of the common risk allele at LOC387715, Ala69Ser, and at CFH, Tyr402His, was assessed in our case-control population, which suggests an additive model indicating an independent contribution of the two gene loci to disease risk. Our data show a disease odds ratio of 57.6 (95% CI: 37.2, 89.0) conferred by homozygosity for risk alleles at both CFH and LOC387715 when compared with the baseline non-risk genotype.

Base Sequence↗
PubMed2005

Common variants in myocardial ion channel genes modify the QT interval in the general population: results from the KORA study.

Altered myocardial repolarization is one of the important substrates of ventricular tachycardia and fibrillation. The influence of rare gene variants on repolarization is evident in familial long QT syndrome. To investigate the influence of common gene variants on the QT interval we performed a linkage disequilibrium based SNP association study of four candidate genes. Using a two-step design we analyzed 174 SNPs from the KCNQ1, KCNH2, KCNE1, and KCNE2 genes in 689 individuals from the population-based KORA study and 14 SNPs with results suggestive of association in a confirmatory sample of 3277 individuals from the same survey. We detected association to a gene variant in intron 1 of the KCNQ1 gene (rs757092, +1.7 ms/allele, P=0.0002) and observed weaker association to a variant upstream of the KCNE1 gene (rs727957, +1.2 ms/allele, P=0.0051). In addition we detected association to two SNPs in the KCNH2 gene, the previously described K897T variant (rs1805123, -1.9 ms/allele, P=0.0006) and a gene variant that tags a different haplotype in the same block (rs3815459, +1.7 ms/allele, P=0.0004). The analysis of additive effects by an allelic score explained a 10.5 ms difference in corrected QT interval length between extreme score groups and 0.951 of trait variance (P<0.00005). These results confirm previous heritability studies indicating that repolarization is a complex trait with a significant heritable component and demonstrate that high-resolution SNP-mapping in large population samples can detect and fine map quantitative trait loci even if locus specific heritabilities are small.

Adult↗
PubMed2005

ALOX5AP gene and the PDE4D gene in a central European population of stroke patients.

BACKGROUND AND PURPOSE: Recent evidence has implicated the genes for 5-lipoxygenase activating protein (ALOX5AP) and phosphodiesterase 4D (PDE4D) as susceptibility genes for stroke in the Icelandic population. The aim of the present study was to explore the role of these genes in a central European population of stroke patients. METHODS: A total of 639 consecutive stroke patients and 736 unrelated population-based controls that had been matched for age and sex were examined using a case-control design. Twenty-two single-nucleotide polymorphisms (SNPs) covering ALOX5AP were genotyped. For PDE4D, microsatellite AC008818-1 and 12 SNPs, which tag all common haplotypes in previously identified linkage disequilibrium (LD) blocks, were analyzed. RESULTS: A nominally significant association with stroke was observed with several SNPs from ALOX5AP, including SNP SG13S114, which had been part of the Icelandic at-risk haplotype. Associations were stronger in males than in females, with SG13S114 (odds ratio, 1.24; 95% CI, 1.04 to 1.55; P=0.017) and SG13S100 (odds ratio, 1.26; 95% CI 1.03 to 1.54; P=0.024) showing the strongest associations. No significant associations were detected with single markers and haplotypes in PDE4D. The frequencies of single-marker alleles and haplotypes differed largely from those in the Icelandic population. CONCLUSIONS: The present study suggests that sequence variants in the ALOX5AP gene are significantly associated with stroke, particularly in males. Variants in the PDE4D gene are not a major risk factor for stroke in individuals from central Europe. Population differences in allele and haplotype frequencies as well as LD structure may contribute to the observed differences between populations.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2005

Linkage disequilibrium patterns and tagSNP transferability among European populations.

The pattern of linkage disequilibrium (LD) is critical for association studies, in which disease-causing variants are identified by allelic association with adjacent markers. The aim of this study is to compare the LD patterns in several distinct European populations. We analyzed four genomic regions (in total, 749 kb) containing candidate genes for complex traits. Individuals were genotyped for markers that are evenly distributed at an average spacing of approximately 2-4 kb in eight population-based samples from ongoing epidemiological studies across Europe. The Centre d'Etude du Polymorphisme Humain (CEPH) trios of the HapMap project were included and were used as a reference population. In general, we observed a conservation of the LD patterns across European samples. Nevertheless, shifts in the positions of the boundaries of high-LD regions can be demonstrated between populations, when assessed by a novel procedure based on bootstrapping. Transferability of LD information among populations was also tested. In two of the analyzed gene regions, sets of tagging single-nucleotide polymorphisms (tagSNPs) selected from the HapMap CEPH trios performed surprisingly well in all local European samples. However, significant variation in the other two gene regions predicts a restricted applicability of CEPH-derived tagging markers. Simulations based on our data set show the extent to which further gain in tagSNP efficiency and transferability can be achieved by increased SNP density.

Alleles↗
PubMed2005

Multiple regions of alpha-synuclein are associated with Parkinson's disease.

alpha-Synuclein is considered to play an important role in the pathogenesis of both the rare familial and the common sporadic forms of Parkinson's disease. Previous reports primarily have tested the association of alpha-synuclein promoter polymorphisms with idiopathic Parkinson's disease, but results are controversial. We first characterized the linkage disequilibrium structure of the alpha-synuclein gene region with a dense set of 56 genetic markers and subsequently performed two independent case-control association analyses using tagging markers. We could distinguish two large linkage disequilibrium blocks spanning the alpha-synuclein gene. Several markers within the 3'-block around exons 5 and 6 showed strong association with Parkinson's disease (p = 0.00009). Effects of the associated variants might be mediated by regulatory elements in this highly conserved region or by a frequency shift in a previously described splice variant lacking exon 5. A direct association with promoter polymorphisms could not be replicated in our sample set. A second set of markers in the 5'-block of the gene were also significantly associated with Parkinson's disease, when young patients and female subjects were analyzed separately. These findings indicate locus heterogeneity for the pathogenesis of Parkinson's disease in different genetic or physiological environments, related to sex and age.

Age Factors↗
PubMed2005

Common variants of LRRK2 are not associated with sporadic Parkinson's disease.

Multiple mutations in the gene for the leucine-rich repeat kinase (LRRK2) cause autosomal dominant late-onset parkinsonism (PARK8). The Gly2019Ser mutation appears to be common in different populations. To investigate whether this novel gene influences the non-Mendelian sporadic form of Parkinson's disease, we genotyped 121 single nucleotide polymorphisms comprehensively covering the entire LRRK2 gene region in a set of 340 Parkinson's disease patients and 680 matched control subjects from Germany. No association could be demonstrated. We have therefore no evidence for the existence of a common variant in LRRK2 that has a strong influence on Parkinson's disease risk.

Age of Onset↗