Biomedical subjects

Thomas Meitinger

Publications and source records attributed to Thomas Meitinger.

40 records · Page 3Linked to original sources

PubMed2003

The epsilon-sarcoglycan gene (SGCE), mutated in myoclonus-dystonia syndrome, is maternally imprinted.

Myoclonus-dystonia syndrome (MDS) is a non-degenerative neurological disorder that has been described to be inherited in an autosomal dominant mode with incomplete penetrance. MDS is caused by loss of function mutations in the epsilon-sarcoglycan gene. Reinvestigation of MDS pedigrees provided evidence for a maternal imprinting mechanism. As differential methylated regions (DMRs) are a characteristic feature of imprinted genes, we studied the methylation pattern of CpG dinucleotides within the CpG island containing the promoter region and the first exon of the SGCE gene by bisulphite genomic sequencing. Our findings revealed that in peripheral blood leukocytes the maternal allele is methylated, while the paternal allele is unmethylated. We also showed that most likely the maternal allele is completely methylated in brain tissue. Furthermore, CpG dinucleotides in maternal and paternal uniparental disomy 7 (UPD7) lymphoblastoid cell lines show a corresponding parent-of-origin specific methylation pattern. The effect of differential methylation on the expression of the SGCE gene was tested in UPD7 cell lines with only a weak RT-PCR signal observed in matUPD7 and a strong signal in patUPD7. These results provide strong evidence for a maternal imprinting of the SGCE gene. The inheritance pattern in MDS families is in agreement with such an imprinting mechanism with the exception of a few cases. We investigated one affected female that inherited the mutated allele from her mother. Surprisingly, we found the paternal wild type allele expressed whereas the mutated maternal allele was not detectable in peripheral blood cDNA.

5-Methylcytosine↗

PubMed2003

X-linked retinitis pigmentosa: RPGR mutations in most families with definite X linkage and clustering of mutations in a short sequence stretch of exon ORF15.

PURPOSE: A comprehensive screening was conducted for RP2 and retinitis pigmentosa GTPase regulator (RPGR) gene mutations including RPGR exon ORF15 in 58 index patients. The frequency of RPGR mutations was assessed in families with definite X-linked recessive disease (xlRP), and a strategy for analyzing the highly repetitive mutational hot spot in exon ORF15 is provided. METHODS: Fifty-eight apparently unrelated index-patients were screened for mutations in all coding exons of the RP2 and the RPGR genes, including splice-sites, by single-strand conformation polymorphism (SSCP) analysis, except for RPGR exon ORF15. A strategy for directly sequencing the large repetitive stretch of exon ORF15 from a 1.6-kb PCR-product was developed. According to pedigree size and evidence for X linkage, families were subdivided into three categories. RESULTS: Screening of 58 xlRP families revealed RP2 mutations in 8% and RPGR mutations in 71% of families with definite X-linked inheritance. Mutations clustered within a approximately 500-bp stretch in exon ORF15. In-frame sequence alterations in exon ORF15 ranged from the deletion of 36 bp to the insertion of 75 bp. CONCLUSIONS: Mutations in the RPGR gene are estimated to cause 15% to 20% of all cases of RP, higher than any other single RP locus. This report provides a detailed strategy to analyze the mutational hot spot in RPGR exon ORF15, which cannot be screened by standard procedures. The discrepancy of the proportion of families linked to the RP3 locus and those having RPGR mutations is resolved in a subset of families with definite X linkage.

Carrier Proteins↗

PubMed2002

Chronic recurrent multifocal osteomyelitis (CRMO): evidence for a susceptibility gene located on chromosome 18q21.3-18q22.

Chronic recurrent multifocal osteomyelitis (CRMO) is characterised by recurrent inflammatory lesions in the metaphyses of long bones and usually affects children and adolescents. Similarity with an autosomal recessive mouse disorder (cmo, chronic multifocal osteomyelitis) prompted us to perform a family based association study with two markers on chromosome 18q in the region homologous to the cmo localisation of the mouse. We found a significant association of CRMO with a rare allele of marker D18S60, resulting in a haplotype relative risk (HRR) of 18. This suggests the existence of a gene in this region contributing in a significant manner to the aetiology of CRMO and concomitantly demonstrates evidence for a genetic basis of CRMO for the first time. This gene is different from RANK, which is mutated in familial expansile osteolysis (FEO), but not in CRMO. Mutation screening in RANK and the genes PIGN and KIAA1468 led to detection of two variants (one in RANK and one in PIGN), which are in linkage disequilibrium with the rare D18S60 allele, but not independently associated with CRMO.

Alleles↗

PubMedDate not supplied

Gene mapping and marker clustering using Shannon's mutual information.

Finding the causal genetic regions underlying complex traits is one of the main aims in human genetics. In the context of complex diseases, which are believed to be controlled by multiple contributing loci of largely unknown effect and position, it is especially important to develop general yet sensitive methods for gene mapping. We discuss the use of Shannon's information theory for population-based gene mapping of discrete and quantitative traits and for marker clustering. Various measures of mutual information were employed in order to develop a comprehensive framework for gene mapping analyses. An algorithm aimed at finding so-called relevance chains of causal markers is proposed. Moreover, entropy measures are used in conjunction with multidimensional scaling to visualize clusters of genetic markers. The relevance chain algorithm successfully detected the two causal regions in a simulated scenario. The approach has also been applied to a published clinical study on autoimmune (Graves') disease. Results were consistent with those of standard statistical methods, but identified an additional locus of interest in the promotor region of the associated gene CTLA4. The developed software is freely available at http://www.Int.ei.tum.de/download/InfoGeneMap/.

Algorithms↗