Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cartilage-hair hypoplasia (CHH), also known as metaphyseal chondrodysplasia McKusick type (OMIM no. 250250), is an autosomal recessive, multi-systemic disease characterized by disproportionate short stature, fine and sparse hair, deficient cellular immunity and a predisposition to malignancy. It is caused by mutations in RMRP, the RNA component of the ribonucleoprotein complex RNase MRP, and, thus, CHH represents one of few Mendelian disorders caused by mutations in a nuclear encoded, non-coding RNA. While studies in yeast indicate that RMRP contributes to diverse cellular functions, the pathogenesis of the human condition is unknown. Studies of our CHH patient cohort revealed mutations in both the promoter and the transcribed region of RMRP. While mutations in the promoter abolished transcription in vitro, RMRP RNA levels in patients with transcribed mutations were also decreased suggesting an unstable RNA. RMRP mutations introduced into the yeast ortholog, NME1, exhibited normal mitochondrial function, chromosomal segregation and cell cycle progression, while a CHH fibroblast cell line exhibited normal mitochondrial content. However, the most commonly found mutation in CHH patients, 70A>G, caused an alteration in ribosomal processing by altering the ratio of the short versus the long form of the 5.8S rRNA in yeast. Transcriptional profiling of CHH patient RNAs showed upregulation of several cytokines and cell cycle regulatory genes, one of which has been implicated in chondrocyte hypertrophy. These data suggest that alteration of ribosomal processing in CHH is associated with altered cytokine signalling and cell cycle progression in terminally differentiating cells in the lymphocytic and chondrocytic cell lineages.
Hum Mol Genet 2005 Dec 01
PMID:Consequences of mutations in the non-coding RMRP RNA in cartilage-hair hypoplasia. 1625 2

Hundreds of gene mutations responsible for Mendelian disorders are currently tested in the clinical laboratory for pre- and postnatal diagnosis, carrier screening and presymptomatic testing. Since human genetic research is currently focused on determining the etiology of complex diseases, including heart disease, diabetes and neuropsychiatric traits, laboratorians will genotype increasing numbers of clinically relevant loci in the future. This will require accurate, high-throughput and cost-effective genotyping platforms, such as the DNA microarray. The Nanogen NanoChip platforms employ hybridization-based technology, using fluorescent detection and electronic control of the target or probe, to obtain clear genotype signal relative to background, and increased flexibility relative to similar chip-based single nucleotide polymorphism genotyping platforms. The scope of this review is intended to describe the operating principle, chips and instrumentation, analyte-specific reagents, published assay protocols, assay development, and clinical use of the NanoChip platforms. It is beyond the scope of this review to describe the use of NanoChip platforms in basic research, and to compare it against all available clinical single nucleotide polymorphism genotyping applications and platforms.
Expert Rev Mol Diagn 2006 May
PMID:Microelectronic array system for molecular diagnostic genotyping: Nanogen NanoChip 400 and molecular biology workstation. 1670 33

The completion of the Human Genome Project has brought the understanding that our genome contains an unexpectedly large proportion of segmental duplications. This poses the challenge of elucidating the consequences of recent duplications on physiology. We have conducted an in-depth study of a subset of segmental duplications on chromosome 16. We focused on PKD1 and ABCC6 duplications because mutations affecting these genes are responsible for the Mendelian disorders autosomal dominant polycystic kidney disease and pseudoxanthoma elasticum, respectively. We establish that duplications of PKD1 and ABCC6 are associated to low-copy repeat 16a and show that such duplications have occurred several times independently in different primate species. We demonstrate that partial duplication of PKD1 and ABCC6 has numerous consequences: the pseudogenes give rise to new transcripts and mediate gene conversion, which not only results in disease-causing mutations but also serves as a reservoir for sequence variation. The duplicated segments are also involved in submicroscopic and microscopic genomic rearrangements, contributing to structural variation in human and chromosomal break points in the gibbon. In conclusion, our data shed light on the recent and ongoing evolution of chromosome 16 mediated by segmental duplication and deepen our understanding of the history of two Mendelian disorder genes.
Mol Biol Evol 2008 Dec
PMID:How segmental duplications shape our genome: recent evolution of ABCC6 and PKD1 Mendelian disease genes. 1879 Oct 38

The application of recent technical developments, such as digital PCR or shot-gun sequencing, for the analysis of cell-free fetal DNA, have indicated that the long-sought goal of the noninvasive detection of Down syndrome may finally be attained. Although these methods are still cumbersome and not high throughput, they provide a paradigm shift in prenatal diagnosis, as they could effectively pronounce the end of invasive procedures, such as amniocentesis or chorionic villous sampling for the detection of such fetal anomalies. However, it remains to be determined how suitable these approaches are for the detection of more subtle fetal genetic alterations, such as those involved in hereditary Mendelian disorders (e.g., thalassemia and cystic fibrosis). New technical developments, such as microfluidics and reliable automated scanning microscopes, have indicated that it may be possible to efficiently retrieve and examine circulating fetal cells. As these contain the entire genomic complement of the fetus, future developments may include the noninvasive determination of the fetal karyotype.
Expert Rev Mol Diagn 2009 Sep
PMID:Noninvasive prenatal diagnosis of fetal aneuploidies and Mendelian disorders: new innovative strategies. 1973 5

Genome-wide association studies (GWAS) have become increasingly widely used to determine regions of the genome which may contain loci influencing the risk of neurological disorders. While linkage studies have identified genes that cause a number of Mendelian disorders, linkage analysis is less well suited for the more common complex disorders. This has led to the widespread use of GWAS for that purpose. Here we present and discuss several of the major extant GWAS in neurological disorders, their limitations, and implications of findings to date.
Curr Mol Med 2009 Sep
PMID:Mining the genome for susceptibility to complex neurological disorders. 1986 Jun 60

Cellular functions are mediated through complex systems of macromolecules and metabolites linked through biochemical and physical interactions, represented in interactome models as 'nodes' and 'edges', respectively. Better understanding of genotype-to-phenotype relationships in human disease will require modeling of how disease-causing mutations affect systems or interactome properties. Here we investigate how perturbations of interactome networks may differ between complete loss of gene products ('node removal') and interaction-specific or edge-specific ('edgetic') alterations. Global computational analyses of approximately 50,000 known causative mutations in human Mendelian disorders revealed clear separations of mutations probably corresponding to those of node removal versus edgetic perturbations. Experimental characterization of mutant alleles in various disorders identified diverse edgetic interaction profiles of mutant proteins, which correlated with distinct structural properties of disease proteins and disease mechanisms. Edgetic perturbations seem to confer distinct functional consequences from node removal because a large fraction of cases in which a single gene is linked to multiple disorders can be modeled by distinguishing edgetic network perturbations. Edgetic network perturbation models might improve both the understanding of dissemination of disease alleles in human populations and the development of molecular therapeutic strategies.
Mol Syst Biol 2009
PMID:Edgetic perturbation models of human inherited disorders. 1988 16

Arterial dissection (AD) is defined as the longitudinal splitting up of the arterial wall caused by intramural bleeding. It can occur as a spontaneous event in all large and medium sized arteries. The histological hallmark of AD is medial degeneration. Histological investigations, gene expression profiling and proteome studies of affected arteries reveal disturbances in many different biological processes including inflammation, proteolytic activity, cell proliferation, apoptosis and smooth muscle cell (SMC) contractile function. Medial degeneration can be caused by various rare dominant Mendelian disorders. Genetic linkage analysis lead to the identification of mutations in different disease-causing genes involved in the biosynthesis of the extracellular matrix (FBN1, COL3A1), in transforming growth factor (TGF) beta signaling (FBN1, TGFBR1, TGFBR2) and in the SMC contractile system (ACTA2, MYH11). Genome wide association studies suggest that the CDKN2A/CDKN2B locus plays a role in the etiology AD and other arterial diseases.
Cell Mol Life Sci 2010 Jun
PMID:Spontaneous arterial dissection: phenotype and molecular pathogenesis. 2015 81

Drug discovery and development has evolved significantly over the last century. Extrapolation from current practice invites speculation about the future in four areas of particular interest. These include the range of therapeutic modalities; the methods for selection of drug targets; the interjection of translational medicine in between the traditional discovery and development phases; and the relationships between institutions. A major focus for the latter three developments is the shortcomings of current target validation. This personal view will be given from perspectives gained in large integrated pharmaceutical companies that are primarily focused on common disorders. Where appropriate, comparisons will be made to the development of treatments for rare Mendelian disorders.
Mol Genet Metab 2010
PMID:Future drug discovery and development. 2018 56

The discovery of 'high-risk' de novo copy number variants (CNVs) associated with neuropsychiatric disorders such as schizophrenia offers the opportunity to translate these findings into useful tools for clinical geneticists. However, this will require estimation of penetrance for these variants, which has not yet been properly considered. To facilitate this process, we estimated the penetrance of CNVs associated with schizophrenia, at 15q13.3, 1q21.1, 15q11.2, 17p12, 2p16.3, 16p13.1 and 16p11.2 with a novel Bayesian method applied to pooled data from published case-control studies. For these CNVs, penetrance for schizophrenia was between 2 and 7.4%, which contrasts with the much higher penetrance for schizophrenia of the 22q11.2 deletions found in velo-cardio-facial syndrome. The highest penetrance was for 15q13.3 deletion (6-9% in individual studies) and the lowest was for 15q11.2 (2%). CNVs confer much higher risk for schizophrenia than common variants, but their penetrance is substantially lower than Mendelian disorders or other syndromic conditions. Since these CNVs predispose to multiple disorders, including epilepsy, autism and intellectual impairment, penetrance estimates will also need to take into account diagnostic specificity, and their overall penetrance for any neuropsychiatric disorder is likely to be much higher. Thus, although CNVs are still far from being clinically useful or relevant to genetic counselling for specific disorders, their detection may hold an important clinical value in predicting negative developmental outcomes.
Hum Mol Genet 2010 Sep 01
PMID:Penetrance for copy number variants associated with schizophrenia. 2058 3

The advent of next-generation sequencing technologies has revolutionized the study of genetic variation in the human genome. Whole-genome sequencing currently represents the most comprehensive strategy for variant detection genome-wide but is costly for large sample sizes, and variants detected in noncoding regions remain largely uninterpretable. By contrast, whole-exome sequencing has been widely applied in the identification of germline mutations underlying Mendelian disorders, somatic mutations in various cancers and de novo mutations in neurodevelopmental disorders. Since whole-exome sequencing focuses upon the entire set of exons in the genome (the exome), it requires additional exome-enrichment steps compared with whole-genome sequencing. Although the availability of multiple commercial exome-enrichment kits has made whole-exome sequencing technically feasible, it has also added to the overall cost. This has led to the emergence of transcriptome (or RNA) sequencing as a potential alternative approach to variant detection within protein coding regions, since the transcriptome of a given tissue represents a quasi-complete set of transcribed genes (mRNAs) and other noncoding RNAs. A further advantage of this approach is that it bypasses the need for exome enrichment. Here we discuss the relative merits and limitations of these approaches as they are applied in the context of variant detection within gene coding regions.
Expert Rev Mol Diagn 2012 Apr
PMID:Exome versus transcriptome sequencing in identifying coding region variants. 2246 15


<< Previous 1 2 3 4 5 Next >>