Human Molecular Genetics - current issue

Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy
Geier, C., Gehmlich, K., Ehler, E., Hassfeld, S., Perrot, A., Hayess, K., Cardim, N., Wenzel, K., Erdmann, B., Krackhardt, F., Posch, M. G., Bublak, A., Nagele, H., Scheffold, T., Dietz, R., Chien, K. R., Spuler, S., Furst, D. O., Nurnberg, P., Ozcelik, C. Tue, 26 Aug 2008 00:00:00 -0000
Hypertrophic cardiomyopathy (HCM) is a frequent genetic cardiac disease and the most common cause of sudden cardiac death in young individuals. Most of the currently known HCM disease genes encode sarcomeric proteins. Previous studies have shown an association between CSRP3 missense mutations and either dilated cardiomyopathy (DCM) or HCM, but all these studies were unable to provide comprehensive genetic evidence for a causative role of CSRP3 mutations. We used linkage analysis and identified a CSRP3 missense mutation in a large German family affected by HCM. We confirmed CSRP3 as an HCM disease gene. Furthermore, CSRP3 missense mutations segregating with HCM were identified in four other families. We used a newly designed monoclonal antibody to show that muscle LIM protein (MLP), the protein encoded by CSRP3, is mainly a cytosolic component of cardiomyocytes and not tightly anchored to sarcomeric structures. Our functional data from both in vitro and in vivo analyses suggest that at least one of MLP’s mutated forms seems to be destabilized in the heart of HCM patients harbouring a CSRP3 missense mutation. We also present evidence for mild skeletal muscle disease in affected persons. Our results support the view that HCM is not exclusively a sarcomeric disease and also suggest that impaired mechano-sensory stress signalling might be involved in the pathogenesis of HCM.
PTHR1 mutations associated with Ollier disease result in receptor loss of function
Couvineau, A., Wouters, V., Bertrand, G., Rouyer, C., Gerard, B., Boon, L. M., Grandchamp, B., Vikkula, M., Silve, C. Tue, 26 Aug 2008 00:00:00 -0000
PTHR1-signaling pathway is critical for the regulation of endochondral ossification. Thus, abnormalities in genes belonging to this pathway could potentially participate in the pathogenesis of Ollier disease/Maffucci syndrome, two developmental disorders defined by the presence of multiple enchondromas. In agreement, a functionally deleterious mutation in PTHR1 (p.R150C) was identified in enchondromas from two of six unrelated patients with enchondromatosis. However, neither the p.R150C mutation (26 tumors) nor any other mutation in the PTHR1 gene (11 patients) could be identified in another study. To further define the role of PTHR1-signaling pathway in Ollier disease and Maffucci syndrome, we analyzed the coding sequences of four genes (PTHR1, IHH, PTHrP and GNAS1) in leucocyte and/or tumor DNA from 61 and 23 patients affected with Ollier disease or Maffucci syndrome, respectively. We identified three previously undescribed missense mutations in PTHR1 in patients with Ollier disease at the heterozygous state. Two mutations (p.G121E, p.A122T) were present only in enchondromas, and one (p.R255H) in both enchondroma and leukocyte DNA. Assessment of receptor function demonstrated that these three mutations impair PTHR1 function by reducing either the affinity of the receptor for PTH or the receptor expression at the cell surface. These mutations were not found in DNA from 222 controls. Including our data, PTHR1 functionally deleterious mutations have now been identified in five out 31 enchondromas from Ollier patients. These findings provide further support for the idea that heterozygous mutations in PTHR1 that impair receptor function participate in the pathogenesis of Ollier disease in some patients.
Hypomethylation of subtelomeric regions in ICF syndrome is associated with abnormally short telomeres and enhanced transcription from telomeric regions
Yehezkel, S., Segev, Y., Viegas-Pequignot, E., Skorecki, K., Selig, S. Tue, 26 Aug 2008 00:00:00 -0000
Telomeres and adjacent subtelomeric regions are packaged as heterochromatin in many organisms. The heterochromatic features include DNA methylation, histones H3-Lys9 (Lysine 9) and H4-Lys20 (Lysine 20) methylation and heterochromatin protein1 alpha binding. Subtelomeric DNA is hypomethylated in human sperm and ova, and these regions are subjected to de novo methylation during development. In mice this activity is carried out by DNA methyltransferase 3b (Dnmt3b). Mutations in DNMT3B in humans lead to the autosomal-recessive ICF (immunodeficiency, centromeric region instability, facial anomalies) syndrome. Here we show that, in addition to several satellite and non-satellite repeats, the subtelomeric regions in lymphoblastoid and fibroblast cells of ICF patients are also hypomethylated to similar levels as in sperm. Furthermore, the telomeres are abnormally short in both the telomerase-positive and -negative cells, and many chromosome ends lack detectable telomere fluorescence in situ hybridization signals from either one or both sister-chromatids. In contrast to Dnmt3a/b–/– mouse embryonic stem cells, increased telomere sister-chromatid exchange was not observed in ICF cells. Hypomethylation of subtelomeric regions was associated in the ICF cells with advanced telomere replication timing and elevated levels of transcripts emanating from telomeric regions, known as TERRA (telomeric-repeat-containing RNA) or TelRNA. The current findings provide a mechanistic explanation for the abnormal telomeric phenotype observed in ICF syndrome and highlights the link between TERRA/TelRNA and structural telomeric integrity.

 

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Genetics, Wageningen - Provides programmes in the area of animal breeding including SIP (Selection Index Program), MAGGIC (Gibbs Sampling) and GENEFLOW. Free software for WIN.

ASReml Cookbook - Statistical software designed for fitting mixed models for large datasets. Contains commented code for univariate and multivariate analysis including longitudinal and spatial analysis.

Big Bench Software - Commercial software for the management of transgenic mouse colonies. Windows and Mac OS X. Demo version available.
Meta Description: [ Big Bench Mouse -- Transgenic mouse colony software. Networkable colony-management database software for Macintosh and Windows. ]

CircuSoft Instrumentation LLC - Transgenic mouse colony tracking and management software for the Mac and Windows. Includes demo software and manuals.

DESIRE - Explore possible selection outcomes when goals (desired gains) are set for traits. This free WIN program is also contained in GENUP.

DFREML - Meyer's variance component estimation software for animal breeding is free for research purposes, available for UNIX, DOS and FORTRAN source code.

500 DRIFT - Graphically represents the effect of genetic drift on gene frequency of one or more populations for a single locus, two allele model in a closed population using stochastic simulation methods. The DOS program is free.

Finnish Forest Genetics and Tree Breeding - Links to population and quantitative genetic software of interest in tree improvement, but also useful in other species.

GeneFlow Inc - This Virginia, USA company provides software (GeneFlow, SynerGene, QTLlocate) and services oriented towards plant breeding. Website does not give prices or operating systems supported.
Meta Description: [ GeneFlow Inc. provides software products and services designed to further the understanding and application of genetic information. ]

Genetic Analysis Software - Extensive list of linkage, mapping and pedigree software with links for obtaining copies.

GeneticStudio - A complete suite of population genetic analysis programs for Mac. Includes plug-in modules. Not updated since 2001.

Genup - Free software to assist learning quantitative genetic concepts (animal breeding) for WIN.

500 Grain Crops Breeding - Access to MQTL (simplified composite QTL mapping), MSIM and GREGOR (genetic simulation) and KIN (kinship coefficients). DOS, UNIX and PASCAL source code is free. From McGill University .

Ignacy Misztal - Animal breeding oriented programs for sparse matrix multiple trait REML and BLUP. Fortran source is free for research use.

Ivory Tower Software - Genetics and breeding simulation software allows students to breed virtual organisms with 2000 genes. The site gives access to a free demo version of the WIN program.
Meta Description: [ Domain name renewal and affordable web hosting packages from Network Solutions ]

Laboratory of Plant Breeding, Wageningen - Offers free downloadable genetics and plant breeding related software.
Meta Description: [ Plant breeding, research and education in the field of genetically improving plants and crops ]

LAMS - Freeware record keeping system designed for a breeding colony of transgenic mice. Includes program description, system requirements, and installation instructions.

Locus Technology, Inc - Colony management, supports creation and tracking of research animals and for transgenic and congenic lines, knockouts and outbred strains.
Meta Description: [ Providing animal management, research and vivarium software programs for data management, analysis, report generation and large or small animal tracking. ]

MapPop - Software for selective mapping and bin mapping. Windows version, documentation and references are available for download.

Pedigree Viewer - Unique display and examination tool for large pedigrees, with inbreeding and genetic merit data also. Free WIN program.

PIGBLUP and BREEDPLAN - Animal Genetics and Breeding Unit of University of New England, Australia have developed BLUP software for genetic selection of swine and beef cattle. Little information is on this site, so ABRI would have to be contacted.

PopGen - Software that models population genetics with emphasis on genetic drift, selection, and migration. Windows 95.

PowerMarker - Set of statistical methods for discrete genetic data analysis, designed especially for microsatellite data analysis. Includes downloadable versions for Windows.
Meta Description: [ Welcome to the home of PowerMarker, a new generation of genetic data analysis for Windows 9x/NT/2x/XP. ]

Progeny Software - Supply pedigree drawing and genetic data management software for genetic research with a built-in customizable relational database.
Meta Description: [ Progeny offers LIMS software for complete sample tracking, genotyping software for whole genome or linkage studies, and pedigree software for family-based clinical data management. ]

500 Quantitative Genetics Resources - List of resources with links to programs and notes on a range of subjects including animal and plant breeding, and evolutionary and human genetics.

R/qtl: A QTL Mapping Environment - Program for mapping quantitative trait loci in experimental crosses. Includes sample graphics and tutorial in pdf format.
Meta Description: [ R/qtl software for mapping quantitative trait loci (QTLs) in experimental crosses. ]

Statistical Genetics Software - Collection of primarily Fortan 77 programs for genetic analysis. Requires registration to download. Site not updated since 1999.

The CompuPed 4.0 Pedigree Program - Extended and reverse pedigrees, inbreeding coefficients and genetic inheritance capabilities for Win and Mac. Download a demo or order online.
Meta Description: [ CompuPed(tm) Millennium is the ultimate pedigree software for Animal Genetics. Presently in use by over 3500 breeders, as well as the genetics classrooms of universities, CompuPed has been, since 1985, the authoritative and accurate expression of genetic information for any species of animal. ]

VCE - Groeneveld's Variance Component Estimation software was developed for animal breeding problems. WIN and UNIX versions are free for research use. PEST documentation is also available here.