Mutations in FKBP10 can cause a severe form of isolated Osteogenesis imperfecta

<p>Abstract</p> <p>Background</p> <p>Mutations in the <it>FKBP10 </it>gene were first described in patients with Osteogenesis imperfecta type III. Two follow up reports found <it>FKBP10 </it>mutations to be associated with Bruck syndrome type 1, a rare disorder characterized by congenital contractures and bone fragility. This raised the question if the patients in the first report indeed had isolated Osteogenesis imperfecta or if Bruck syndrome would have been the better diagnosis.</p> <p>Methods</p> <p>The patients described here are affected by severe autosomal recessive Osteogenesis imperfecta without contractures.</p> <p>Results</p> <p>Homozygosity mapping identified <it>FKBP10 </it>as a candidate gene, and sequencing revealed a base pair exchange that causes a C-terminal premature stop codon in this gene.</p> <p>Conclusions</p> <p>Our study demonstrates that <it>FKBP10 </it>mutations not only cause Bruck syndrome or Osteogenesis imperfecta type III but can result in a severe type of isolated Osteogenesis imperfecta type IV with prenatal onset. Furthermore, it adds dentinogenesis imperfecta to the spectrum of clinical symptoms associated with <it>FKBP10 </it>mutations.</p

Functional Annotation and Identification of Candidate Disease Genes by Computational Analysis of Normal Tissue Gene Expression Data

Background: High-throughput gene expression data can predict gene function through the ‘‘guilt by association’ ’ principle: coexpressed genes are likely to be functionally associated. Methodology/Principal Findings: We analyzed publicly available expression data on normal human tissues. The analysis is based on the integration of data obtained with two experimental platforms (microarrays and SAGE) and of various measures of dissimilarity between expression profiles. The building blocks of the procedure are the Ranked Coexpression Groups (RCG), small sets of tightly coexpressed genes which are analyzed in terms of functional annotation. Functionally characterized RCGs are selected by means of the majority rule and used to predict new functional annotations. Functionally characterized RCGs are enriched in groups of genes associated to similar phenotypes. We exploit this fact to find new candidate disease genes for many OMIM phenotypes of unknown molecular origin. Conclusions/Significance: We predict new functional annotations for many human genes, showing that the integration of different data sets and coexpression measures significantly improves the scope of the results. Combining gene expression data, functional annotation and known phenotype-gene associations we provide candidate genes for several geneti

Chromosomal localization of 15 ion channel genes

Several human Mendelian diseases, including the long-QT syndrome, malignant hyperthermia, and episodic ataxia/myokymia syndrome, have recently been demonstrated to be due to mutations in ion channel genes. Systematic mapping of ion channel genes may therefore reveal candidates for other heritable disorders. In this study, the GenBank and dbEST databases were used to identify members of several ion channel families (voltage-gated calcium and sodium cardiac chloride, and all classes of potassium channels). Genes and ESTs without prior map localization were identified based on GDB and OWL database information and 15 genes and ESTs were selected for mapping. Of these 15, only the serotonin receptor 5HT3R had been previously mapped to a chromosome. A somatic cell hybrid panel (SCH) was screened with an STS from each gene and, if necessary, the results verified by a second SCH panel. For three ESTs, rodent derived PCR products of the same size as the human STS precluded SCH mapping. For these three, human Pl clones were isolated and the genomic location was determined by metaphase FISH. These genes and ESTs can now be further evaluated as candidate genes for inherited cardiac, neuromuscular, and psychiatric disorders mapped to these chromosomes. Furthermore, the ESTs developed in this study can be used to isolate genomic clones, enabling the determination of each transcript's genomic structure and physical map location. This approach may also be applicable to other gene families and may aid in the identification of candidate genes for groups of related heritable disorders.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45548/1/11188_2006_Article_BF02369898.pd

Third Report on Chicken Genes and Chromosomes 2015

Following on from the First Report on Chicken Genes and Chromosomes [Schmid et al., 2000] and the Second Report in 2005 [Schmid et al., 2005], we are pleased to publish this long-awaited Third Report on the latest developments in chicken genomics. The First Report highlighted the availability of genetic and physical maps, while the Second Report was published as the chicken genome sequence was released. This report comes at a time of huge technological advances (particularly in sequencing methodologies) which have allowed us to examine the chicken genome in detail not possible until now. This has also heralded an explosion in avian genomics, with the current availability of more than 48 bird genomes [Zhang G et al., 2014b; Eöry et al., 2015], with many more planned

Using C. elegans to decipher the cellular and molecular mechanisms underlying neurodevelopmental disorders

Prova tipográfica (uncorrected proof)Neurodevelopmental disorders such as epilepsy, intellectual disability (ID), and autism spectrum disorders (ASDs) occur in over 2 % of the population, as the result of genetic mutations, environmental factors, or combination of both. In the last years, use of large-scale genomic techniques allowed important advances in the identification of genes/loci associated with these disorders. Nevertheless, following association of novel genes with a given disease, interpretation of findings is often difficult due to lack of information on gene function and effect of a given mutation in the corresponding protein. This brings the need to validate genetic associations from a functional perspective in model systems in a relatively fast but effective manner. In this context, the small nematode, Caenorhabditis elegans, presents a good compromise between the simplicity of cell models and the complexity of rodent nervous systems. In this article, we review the features that make C. elegans a good model for the study of neurodevelopmental diseases. We discuss its nervous system architecture and function as well as the molecular basis of behaviors that seem important in the context of different neurodevelopmental disorders. We review methodologies used to assess memory, learning, and social behavior as well as susceptibility to seizures in this organism. We will also discuss technological progresses applied in C. elegans neurobiology research, such as use of microfluidics and optogenetic tools. Finally, we will present some interesting examples of the functional analysis of genes associated with human neurodevelopmental disorders and how we can move from genes to therapies using this simple model organism.The authors would like to acknowledge Fundação para a Ciência e Tecnologia (FCT) (PTDC/SAU-GMG/112577/2009). AJR and CB are recipients of FCT fellowships: SFRH/BPD/33611/2009 and SFRH/BPD/74452/2010, respectively

[Avian cytogenetics goes functional] Third report on chicken genes and chromosomes 2015

High-density gridded libraries of large-insert clones using bacterial artificial chromosome (BAC) and other vectors are essential tools for genetic and genomic research in chicken and other avian species... Taken together, these studies demonstrate that applications of large-insert clones and BAC libraries derived from birds are, and will continue to be, effective tools to aid high-throughput and state-of-the-art genomic efforts and the important biological insight that arises from them

Mutated nicotinic receptors responsible for autosomal dominant nocturnal frontal lobe epilepsy are more sensitive to carbamazepine

The recent linkage between a genetically transmissible form of epilepsy (ADNFLE) and mutations within the alpha4 subunit, one component of the major brain neuronal nicotinic acetylcholine receptor (nAChR), raises the question of the role of this receptor in epileptogenesis. Although acting by different mechanisms, the two genetic alterations so far identified both render the nAChR less efficient. In view of the high sensitivity of ADNFLE to carbamazepine (CBZ), we studied the effects of this drug and of valproate (VPA) on the human alpha4beta2 nAChR and its mutations