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Inherited Diseases (inherited + disease)
Kinds of Inherited Diseases Selected AbstractsEditorial: DNA Testing for Inherited Diseases in AnimalsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 3 2004Julie A.L. Cavanagh BScAgr No abstract is available for this article. [source] A review of genetic disorders of hypopigmentation: lessons learned from the biology of melanocytesEXPERIMENTAL DERMATOLOGY, Issue 9 2009Clio Dessinioti Abstract:, Inherited diseases of pigmentation were among the first traits studied in humans because of their easy recognition. The discovery of genes that regulate melanocytic development and function and the identification of disease-causative mutations have greatly improved our understanding of the molecular basis of pigmentary genodermatoses and their underlying pathogenetic mechanisms. Pigmentation mutants can account for hypo-/amelanosis, with or without altered melanocyte number, resulting in different phenotypes, such as Waardenburg syndrome, piebaldism, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, oculocutaneous albinism and Griscelli syndrome. In this review, we summarize the basic concepts of melanocyte biology and discuss how molecular defects in melanocyte development and function can result in the development of hypopigmentary hereditary skin diseases. [source] Pregnancy outcome in congenital dyserythropoietic anemia type IEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 4 2008Hanna Shalev Abstract Objectives:, Congenital dyserythropoietic anemia type I (CDA I) is a rare inherited disease characterized by moderate to severe macrocytic anemia and abnormal erythroid precursors with nuclear chromatin bridges and spongy heterochromatin. Moderate to severe maternal anemia is a recognized independent risk factor for low birth weight (LBW) and complicated delivery. The aim of the study was to review the outcome of pregnancies in women with CDA I. Methods:, The clinical and laboratory records of 28 spontaneous pregnancies in six Bedouin women with CDA I were reviewed. The results were compared with findings from a retrospective review of a large population-based registry including all pregnancies in Bedouin women during the same 15-yr period. Results:, Eighteen pregnancies in women with CDA I (64%) were complicated. One pregnancy was aborted spontaneously in the first trimester and one resulted in a non-viable fetus (stillborn at 26 wk). Cesarean section (CS) was performed in 10 pregnancies (36%). Eleven of the 26 newborns (42%) had a LBW: six were born prematurely and five were small for gestational age. The odds ratio for CS in women with CDA I compared with healthy Bedouin women was 4.5 [95% confidence interval (CI) 1.2,10.3], and for a LBW infant, 5.5 (95% CI 2.4,12.3). Careful follow-up was associated with significantly better fetal outcome (P = 0.05). Conclusions:, Pregnancies in women with CDA I are at high risk for delivery-related and outcome complications. To improve fetal outcome, women with CDA I should be carefully monitored during pregnancy. [source] Gene conversion causing human inherited disease: Evidence for involvement of non-B-DNA-forming sequences and recombination-promoting motifs in DNA breakage and repair,HUMAN MUTATION, Issue 8 2009Nadia Chuzhanova Abstract A variety of DNA sequence motifs including inverted repeats, minisatellites, and the , recombination hotspot, have been reported in association with gene conversion in human genes causing inherited disease. However, no methodical statistically based analysis has been performed to formalize these observations. We have performed an in silico analysis of the DNA sequence tracts involved in 27 nonoverlapping gene conversion events in 19 different genes reported in the context of inherited disease. We found that gene conversion events tend to occur within (C+G)- and CpG-rich regions and that sequences with the potential to form non-B-DNA structures, and which may be involved in the generation of double-strand breaks that could, in turn, serve to promote gene conversion, occur disproportionately within maximal converted tracts and/or short flanking regions. Maximal converted tracts were also found to be enriched (P<0.01) in a truncated version of the ,-element (a TGGTGG motif), immunoglobulin heavy chain class switch repeats, translin target sites and several novel motifs including (or overlapping) the classical meiotic recombination hotspot, CCTCCCCT. Finally, gene conversions tend to occur in genomic regions that have the potential to fold into stable hairpin conformations. These findings support the concept that recombination-inducing motifs, in association with alternative DNA conformations, can promote recombination in the human genome. Hum Mutat 30:1,10, 2009. © 2009 Wiley-Liss, Inc. [source] IBDfinder and SNPsetter: Tools for pedigree-independent identification of autozygous regions in individuals with recessive inherited disease,HUMAN MUTATION, Issue 6 2009Ian M. Carr Abstract Autozygosity mapping of recessive genes can be performed on a small number of affected individuals from consanguineous pedigrees. With the advent of microarray SNP analysis, acquiring genotype data has become extremely simple and quick, in comparison to gene mapping with microsatellite markers. However, the subsequent data analysis required to identify autozygous regions can still be a significant obstacle. For rapid gene identification, it may be desirable to integrate information from heterogeneous groups of affected individuals, both familial and isolated, under various assumptions of ancestry and locus heterogeneity, that are not amenable to formal linkage analysis. Unfortunately, there are few computer programs aimed specifically at facilitating this type of data sifting. Here, we demonstrate two new programs that facilitate the identification of autozygous regions within a heterogeneous SNP dataset derived from familial and sporadic affected individuals. Hum Mutat 30:1,8, 2009. © 2009 Wiley-Liss, Inc. [source] Cardiac Calsequestrin: The New Kid on the Block in ArrhythmiasJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 10 2009NAGESH CHOPRA M.D. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited disease characterized by physical or emotional stress-induced ventricular arrhythmias in the absence of any structural heart disease or QT prolongation. Thus far, mutations in genes encoding the sarcoplasmic reticulum Ca2+ release channel (RYR2) and the sarcoplasmic reticulum Ca2+ binding protein cardiac calsequestrin (CASQ2) have been identified in CPVT patients. Here, we review the role of cardiac calsequestrin in health and disease, with a particular focus on how calsequestrin deficiency can cause arrhythmia susceptibility. Clinical implications and a promising new drug therapy for CPVT are discussed. [source] Comments on ,Significance of developmental expression of amphioxus Branchiostoma belcheri and zebrafish Danio rerio Hsd17b10 in biological and medical research'JOURNAL OF FISH BIOLOGY, Issue 8 2009X. He The reported data on the developmental expression of Hsd17b10 gene in Danio rerio is crucial to the utilization of the D. rerio embryo as an animal model for human developmental disorders caused either by mutations on HSD17B10 (formerly HADH2) or by defective expression of the gene. Related diseases were summarized, and it was noticed that hyperinsulinaemic hypoglycaemia is not linked to HSD17B10. This inherited disease is actually caused by a deletion in the HADH gene on chromosome 4. Moreover, it was found by a revision of the reported phylogenetic tree that hydroxyacyl-CoA dehydrogenase II or rather hydroxysteroid (17beta) dehydrogenase 10 (HSD10) of amphioxus Branchiostoma belcheri,occupies a transition position from HSD10 orthologs of invertebrates to those of vertebrates. [source] Resolving a genetic paradox throughout preimplantation genetic diagnosis for autosomal dominant severe congenital neutropeniaPRENATAL DIAGNOSIS, Issue 3 2010Mira Malcov Abstract Objective Severe congenital neutropenia is an inherited disease characterized by low peripheral blood neutrophils, amenable to bone marrow transplantation. Genetic analysis in the family here described detected a ELA2 splice-site mutation in the affected child and also in his asymptomatic father. The parents requested preimplantation genetic diagnosis (PGD), coupled with HLA matching, to obtain a suitable bone marrow donor for the affected child. Methods A PGD protocol was developed, based on multiplex nested PCR for direct analysis of the ELA2 mutation, flanking polymorphic markers and HLA typing. Results The amplification efficiency of the mutation was > 90% in single leukocytes from the affected child but only 67% in the father. Analysis of single haploid sperm cells from the father demonstrated three different sperm-cell populations: (1) sperm cells harboring the ELA2 mutation on the ,affected' haplotype, (2) sperm cells without the ELA2 mutation on the ,normal' haplotype, and (3) sperm cells without the ELA2 mutation on the ,affected' haplotype. Conclusion These data demonstrate that the ELA2 mutation in the father occurred de novo during his embryonic development, resulting in somatic as well as germ-line mosaicism. This conclusion was also taken into consideration when PGD was performed. Copyright © 2010 John Wiley & Sons, Ltd. [source] Prenatal diagnosis of carnitine palmitoyltransferase 2 deficiency in chorionic villi: a novel approachPRENATAL DIAGNOSIS, Issue 11 2003Bernadette Chadefaux Vekemans Abstract Carnitine palmitoyltransferase 2 (CPT2) deficiency, the most common autosomal recessive inherited disease of the mitochondrial long-chain fatty acid (LCFA) ,-oxidation, may result in three distinct clinical phenotypes, namely, a mild adult muscular form, a severe infantile hepatocardiomuscular disease, and a neonatal form, which includes dysmorphic features in addition to hepatocardiomuscular symptoms. Both the latter forms are life-threatening diseases, and prenatal diagnosis (PND) can be offered to couples at a one-fourth risk of having an affected child. PND of CPT2 deficiency hitherto relied mostly on mutation detection from fresh chorionic villi (10 weeks' gestation), since CPT2 activity could be assayed on cultured amniocytes only (16,17 weeks' gestation). We devised a CPT2 activity assay from 10 mg of chorionic villi sampling (CVS). Combining this enzymatic assay to haplotype study using polymorphic markers linked to the CPT2 gene, we were able to carry out within 2 days, CPT2 deficiency PND, in two unrelated families, using a CVS performed at the 11th week of gestation. Copyright © 2003 John Wiley & Sons, Ltd. [source] Partial phenotypic correction and immune tolerance induction to enzyme replacement therapy after hematopoietic stem cell gene transfer of ,-glucosidase in Pompe diseaseTHE JOURNAL OF GENE MEDICINE, Issue 4 2009Gaëlle Douillard-Guilloux Abstract Background Glycogen storage disease type II (GSDII) or Pompe disease is an inherited disease of glycogen metabolism caused by a lack of functional lysosomal acid ,-glucosidase (GAA). Affected individuals store glycogen in lysosomes resulting in fatal hypertrophic cardiomyopathy and respiratory failure in the most severe form. Even if enzyme replacement therapy (ERT) has already proven some efficacy, its results remain heterogeneous in skeletal muscle, especially in cross reactive immunological material (CRIM)-negative patients. We investigated for the first time the use of hematopoietic stem cell (HSC) gene therapy in a murine model of GSDII. Methods Deficient HSC were transduced with a lentiviral vector expressing human GAA or enhanced green fluorescent protein (GFP) under the control of the retroviral MND promoter and transplanted into lethally irradiated GSDII mice. Animals were then subjected to an ERT protocol for 5 weeks and monitored for metabolic correction and GAA-induced immune reaction. Results GAA was expressed as a correctly processed protein, allowing a complete enzymatic correction in transduced deficient cells without toxicity. Seventeen weeks after transplantation, a partial restoration of the GAA enzymatic activity was observed in bone marrow and peripheral blood cells of GSDII mice, allowing a significant glycogen clearance in skeletal muscle. ERT induced a robust antibody response in GFP-transplanted mice, whereas no immune reaction could be detected in GAA-transplanted mice. Conclusions Lentiviral vector-mediated HSC gene therapy leads to a partial metabolic correction and induces a tolerance to ERT in GSDII mice. This strategy could enhance the efficacy of ERT in CRIM-negative Pompe patients. Copyright © 2009 John Wiley & Sons, Ltd. [source] Enhanced transthyretin tetramer stability following expression of an amyloid disease transsuppressor variant in mammalian cellsTHE JOURNAL OF GENE MEDICINE, Issue 2 2009Masakazu Kamata Abstract Background The transthyretin (TTR) amyloidosis is an incurable fatal inherited disease that is characterized by progressive peripheral and autonomic neuropathy. It is caused by missense amyloidogenic mutations in the TTR gene that destabilize the native tetrameric state and lead to the cytotoxic misfolded monomeric state. One interesting variant (T119M) stabilizes heterotetramers with amyloidogenic TTR and, in the reported heterozygous individuals, protects the carriers from disease. In the present study, we characterize in vitro and in vivo the ectopic expression of the human T119M mutant, termed a transsuppressor for TTR amyloid disease. Methods Lentiviral vectors encoding wild or mutant forms of human TTR were constructed and transduced to the human hepatocellular carcinoma cell line, HepG2, or mice. Heterooligomerization between T119M TTR and amyloidogenic variants was analysed by immunoprecipitation following western blotting. Results T119M TTR was stably expressed in transduced HepG2 cells and was secreted as an oligomer that can interact with its native partner, retinol-binding protein. Importantly, the T119M TTR formed secreted heterooligomers with amyloidogenic TTR variants, V30M, L55P and V122I, in HepG2 cells that were more stable than the homooligomers of the same amyloidogenic TTR variants. Human T119M TTR also formed heterooligomers with V30M TTR in transduced mice. Conclusions The results obtained in the present study demonstrate the stabilization of heterotetramers by T119M TTR in human cells and suggest that gene transfer of T119M TTR may have potential as a gene therapy for TTR amyloidosis. Copyright © 2008 John Wiley & Sons, Ltd. [source] A bicistronic SIN-lentiviral vector containing G156A MGMT allows selection and metabolic correction of hematopoietic protoporphyric cell linesTHE JOURNAL OF GENE MEDICINE, Issue 9 2003Emmanuel Richard Abstract Background Erythropoietic protoporphyria (EPP) is an inherited disease characterised by a ferrochelatase (FECH) deficiency, the latest enzyme of the heme biosynthetic pathway, leading to the accumulation of toxic protoporphyrin in the liver, bone marrow and spleen. We have previously shown that a successful gene therapy of a murine model of the disease was possible with lentiviral vectors even in the absence of preselection of corrected cells, but lethal irradiation of the recipient was necessary to obtain an efficient bone marrow engraftment. To overcome a preconditioning regimen, a selective growth advantage has to be conferred to the corrected cells. Methods We have developed a novel bicistronic lentiviral vector that contains the human alkylating drug resistance mutant O6 -methylguanine DNA methyltransferase (MGMT G156A) and FECH cDNAs. We tested their capacity to protect hematopoietic cell lines efficiently from alkylating drug toxicity and correct enzymatic deficiency. Results EPP lymphoblastoid (LB) cell lines, K562 and cord-blood-derived CD34+ cells were transduced at a low multiplicity of infection (MOI) with the bicistronic constructs. Resistance to O6 -benzylguanine (BG)/N,N,-bis(2-chloroethyl)- N -nitrosourea (BCNU) was clearly shown in transduced cells, leading to the survival and expansion of provirus-containing cells. Corrected EPP LB cells were selectively amplified, leading to complete restoration of enzymatic activity and the absence of protoporphyrin accumulation. Conclusions This study demonstrates that a lentiviral vector including therapeutic and G156A MGMT genes followed by BG/BCNU exposure can lead to a full metabolic correction of deficient cells. This vector might form the basis of new EPP mouse gene therapy protocols without a preconditioning regimen followed by in vivo selection of corrected hematopoietic stem cells. Copyright © 2003 John Wiley & Sons, Ltd. [source] Inhibition of defective adenylosuccinate lyase by HNE: A neurological disease that may be affected by oxidative stressBIOFACTORS, Issue 1-4 2005C. Crifò Abstract Adenylosuccinate lyase is an enzyme of fumarase superfamily that participates in the purine biosynthetic pathway, catalysing the nonhydrolytic cleavage of succinyl groups from SAICA ribotide and adenylosuccinate. Enzyme defects are associated with a human inherited disease, which arises from single point mutations to the gene and results in mild to severe psychomotor retardation, epilepsy, muscle wasting, and autistic features. Adenylosuccinate lyase activity is lost to a different extent in the patients. Diminished levels of enzyme have been attributed to loss of catalytic activity, protein instability, or environmental factors. P100A/D422Y mutation represents a feasible model for studying the effect of cell milieu on the activity of the impaired enzyme. The defective enzyme is inhibited by micromolar concentrations of trans-4-hydroxy-2-nonenal (HNE), a major product of membrane peroxidation that has been found to accumulate in brain tissues of patients with neurodegenerative disorders. It is suggested that inactivation of defective adenylosuccinate lyase by HNE and other membrane peroxidation products may account, at least in part, for the impairment of neurological functions and recurrent worsening of the symptoms. [source] Very early detection of RET proto-oncogene mutation is crucial for preventive thyroidectomy in multiple endocrine neoplasia type 2 childrenCANCER, Issue 2 2002Presence of C-cell malignant disease in asymptomatic carriers Abstract BACKGROUND Multiple endocrine neoplasia type 2 (MEN 2) is an inherited disease caused by germline mutations in the RET proto-oncogene, and is responsible for the development of endocrine neoplasia. Its prognosis is dependent on the appearance and spread of medullary thyroid carcinoma (MTC). Relatives at risk can be identified before clinical or biochemical signs of the disease become evident. METHODS Twenty-one families with MEN 2 (16 families with MEN 2A and 5 families with MEN 2B) were studied. Peripheral blood DNA was amplified by polymerase chain reaction. DNA sequence or restriction enzyme analysis was performed to detect mutations of RET proto-oncogene exons 10, 11, and 16. Molecular analysis was carried out in all index patients as well as in 98 relatives of MEN 2A patients (60 juveniles, ages 6 months to 21 years, and 38 adults, ages 22 to 81 years) and in 13 relatives (6 juveniles ages 10 to 21 years, and 7 adults ages 41 to 66 years) from MEN 2B families. RESULTS Molecular studies showed a mutation at codon 634, exon 11 in all MEN 2A patients. All MEN 2B patients showed an ATG to ACG (Met918Thr) mutation. In MEN 2A families, 42 out of 98 relatives were affected. Total thyroidectomy was performed in 18 juvenile carriers ages 17 months to 21 years. Histopathologic studies of the glands revealed parafollicular cell (C-cell) hyperplasia in all of these carriers, medullary thyroid carcinoma in 15 carriers, and only one carrier with lymph node metastases. CONCLUSIONS The consistent finding of C-cell disease in all the juvenile carriers who underwent preventive thyroidectomy emphasizes the relevance of early screening in children at risk of developing MTC. The presence of MTC in the specimen of prophylactic thyroidectomy from a 17 month old girl highlights the importance of thyroidectomy as soon as the molecular diagnosis is confirmed. Cancer 2002;94:323,30. © 2002 American Cancer Society. [source] 3331: The genetics of corneal dystrophiesACTA OPHTHALMOLOGICA, Issue 2010GCM BLACK Purpose To provide an overview of progress in understanding of the genetics of corneal dystrophies. Methods A systematic review, including case presentations, to illustrate insights into genes underlying inherited corneal dystrophies: Results Recent advances have extended our undestanding of the causation of a range of classical inherited corneal dystrophies. This includes the identifcation of genes underlying superficial (e.g Meesmann, KRT3/KRT12), stromal (BIGH3/TGFB1) and endothelial (SLC4A11, COL8A2) dysrophies. Understanding of less well-recognised phenotypes (e.g brittle cornea syndrome) has also shed light on the regulation of corneal homeostasis including the control of corneal thickness. Conclusion Identification of the genes underlying corneal inherited disease improves diagnosis of corneal dysrophies, sheds light on disease mechanisms and has potential to improve patient management. In the futuire this will lead to new therapeutic modalities for an important group of conditions associated with significant visual loss. [source] Remodelling of collagen fibrils and proteoglycans in the zebrafish cornea during developmentACTA OPHTHALMOLOGICA, Issue 2007S AKHTAR Purpose: Collagen fibrils and proteoglycans are the main components of the corneal extracellular matrix and corneal transparency depends crucially on their proper organisation. We investigated their formation and arrangement in the developing cornea of the zebrafish, a major model of vertebrate development and genetic disease. Methods: We employed thin-section electron microscopy to investigate the ultrastructure of the zebrafish cornea at different stages of development. Results: Layering of the zebrafish cornea into an epithelium, Bowman's layer, stroma and endothelium was observed by 72 hours post-fertilization. At this stage, the stroma contained orthogonally arranged collagen fibrils and small proteoglycans. The density of proteoglycans increased gradually throughout subsequent development. In the stroma of 2 week old larvae, the collagen fibrils were organized into thin lamellae for the first time and were separated by very large, randomly distributed proteoglycans. At 4 weeks, a regular arrangement of proteoglycans around the collagen fibrils was observed for the first time and the lamellae also thickened. Conclusions: This is the first report of collagen fibril and proteoglycan development in the zebrafish cornea and it directly correlates collagen fibril and proteoglycan organisation of the zebrafish cornea with that of the human cornea. The similarities between the two species, including the possession of a Bowman layer, suggest that the zebrafish could serve as a model for the genetics of human corneal development and inherited disease. [source] A novel mutation of the WRN gene in a Chinese patient with Werner syndromeCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 3 2008N. Zhao Summary Werner syndrome (WS) is an autosomal recessive inherited disease characterized by features of premature ageing. It is caused by mutations of the WRN gene encoding a protein with both exonuclease and helicase activities. The aim of this study was to identify gene mutations in a Chinese patient with WS. A 31-year-old Chinese man with typical features of WS was diagnosed as having probable WS. We performed PCR to scan 33 exons of the WRN gene of the patient, six members of his family, and 50 unrelated controls. Automated DNA sequencing identified the mutation in the patient as 3250delG. The proband's parents, son, younger brother and paternal grandmother were heterozygous. We did not find this heterozygous mutation in the proband's maternal grandmother or in any of 50 normal controls. The novel mutation in the WRN gene is responsible for the pathogenesis of WS and genetic detection is a useful method to confirm the diagnosis. [source] Revealing the human mutomeCLINICAL GENETICS, Issue 4 2010JM Chen Chen JM, Férec C, Cooper DN. Revealing the human mutome. The number of known mutations in human nuclear genes, underlying or associated with human inherited disease, has now exceeded 100,000 in more than 3700 different genes (Human Gene Mutation Database). However, for a variety of reasons, this figure is likely to represent only a small proportion of the clinically relevant genetic variants that remain to be identified in the human genome (the ,mutome'). With the advent of next-generation sequencing, we are currently witnessing a revolution in medical genetics. In particular, whole-genome sequencing (WGS) has the potential to identify all disease-causing or disease-associated DNA variants in a given individual. Here, we use examples of recent advances in our understanding of mutational/pathogenic mechanisms to guide our thinking about possible locations outwith gene-coding sequences for those disease-causing or disease-associated variants that are likely so often to have been overlooked because of the inadequacy of current mutation screening protocols. Such considerations are important not only for improving mutation-screening strategies but also for enhancing the interpretation of findings derived from genome-wide association studies, whole-exome sequencing and WGS. An improved understanding of the human mutome will not only lead to the development of improved diagnostic testing procedures but should also improve our understanding of human genome biology. [source] Equine clinical genomics: A clinician's primerEQUINE VETERINARY JOURNAL, Issue 7 2010M. M. BROSNAHAN Summary The objective of this review is to introduce equine clinicians to the rapidly evolving field of clinical genomics with a vision of improving the health and welfare of the domestic horse. For 15 years a consortium of veterinary geneticists and clinicians has worked together under the umbrella of The Horse Genome Project. This group, encompassing 22 laboratories in 12 countries, has made rapid progress, developing several iterations of linkage, physical and comparative gene maps of the horse with increasing levels of detail. In early 2006, the research was greatly facilitated when the US National Human Genome Research Institute of the National Institutes of Health added the horse to the list of mammalian species scheduled for whole genome sequencing. The genome of the domestic horse has now been sequenced and is available to researchers worldwide in publicly accessible databases. This achievement creates the potential for transformative change within the horse industry, particularly in the fields of internal medicine, sports medicine and reproduction. The genome sequence has enabled the development of new genome-wide tools and resources for studying inherited diseases of the horse. To date, researchers have identified 11 mutations causing 10 clinical syndromes in the horse. Testing is commercially available for all but one of these diseases. Future research will probably identify the genetic bases for other equine diseases, produce new diagnostic tests and generate novel therapeutics for some of these conditions. This will enable equine clinicians to play a critical role in ensuring the thoughtful and appropriate application of this knowledge as they assist clients with breeding and clinical decision-making. [source] The heat shock protein 70 molecular chaperone network in the pancreatic endoplasmic reticulum , a quantitative approachFEBS JOURNAL, Issue 19 2007Andreas Weitzmann Traditionally, the canine pancreatic endoplasmic reticulum (ER) has been the workhorse for cell-free studies on protein transport into the mammalian ER. These studies have revealed multiple roles for the major ER-luminal heat shock protein (Hsp) 70, IgG heavy chain-binding protein (BiP), at least one of which also involves the second ER-luminal Hsp70, glucose-regulated protein (Grp) 170. In addition, at least one of these BiP activities depends on Hsp40. Up to now, five Hsp40s and two nucleotide exchange factors, Sil1 and Grp170, have been identified in the ER of different mammalian cell types. Here we quantified the various proteins of this chaperone network in canine pancreatic rough microsomes. We also characterized the various purified proteins with respect to their affinities for BiP and their effect on the ATPase activity of BiP. The results identify Grp170 as the major nucleotide exchange factor for BiP, and the resident ER-membrane proteins ER-resident J-domain protein 1 plus ER-resident J-domain protein 2/Sec63 as prime candidates for cochaperones of BiP in protein transport in the pancreatic ER. Thus, these data represent a comprehensive analysis of the BiP chaperone network that was recently linked to two human inherited diseases, polycystic liver disease and Marinesco,Sjögren syndrome. [source] UMD-predictor, a new prediction tool for nucleotide substitution pathogenicity,application to four genes: FBN1, FBN2, TGFBR1, and TGFBR2,HUMAN MUTATION, Issue 6 2009Mélissa Yana Frédéric Abstract Approximately half of gene lesions responsible for human inherited diseases are due to an amino acid substitution, showing that this mutational mechanism plays a large role in diseases. Distinguishing neutral sequence variations from those responsible for the phenotype is of major interest in human genetics. Because in vitro validation of mutations is not always possible in diagnostic settings, indirect arguments must be accumulated to define whether a missense variation is causative. To further differentiate neutral variants from pathogenic nucleotide substitutions, we developed a new tool, UMD-Predictor®. This tool provides a combinatorial approach that associates the following data: localization within the protein, conservation, biochemical properties of the mutant and wild-type residues, and the potential impact of the variation on mRNA. To evaluate this new tool, we compared it to the SIFT, PolyPhen, and SNAP software, the BLOSUM62 and Yu's Biochemical Matrices. All tools were evaluated using variations from well-validated datasets extracted from four UMD,LSDB databases (UMD,FBN1, UMD,FBN2, UMD,TGFBR1, and UMD,TGFBR2) that contain all published mutations of the corresponding genes, that is, 1,945 mutations, among which 796 different substitutions corresponding to missense mutations. Our results show that the UMD-Predictor® algorithm is the most efficient tool to predict pathogenic mutations in this context with a positive predictive value of 99.4%, a sensitivity of 95.4%, and a specificity of 92.2%. It can thus enhance the interpretation of variations in these genes, and could easily be applied to any other disease gene through the freely available UMD® generic software (http://www.umd.be). Hum Mutat 30:1,8, 2009. © 2009 Wiley-Liss, Inc. [source] Validation of microarray-based resequencing of 93 worldwide mitochondrial genomes,HUMAN MUTATION, Issue 1 2009Anne Hartmann Abstract The human mitochondrial genome consists of a multicopy, circular dsDNA molecule of 16,569 base pairs. It encodes for 13 proteins, two ribosomal genes, and 22 tRNAs that are essential in the generation of cellular ATP by oxidative phosphorylation in eukaryotic cells. Germline mutations in mitochondrial DNA (mtDNA) are an important cause of maternally inherited diseases, while somatic mtDNA mutations may play important roles in aging and cancer. mtDNA polymorphisms are also widely used in population and forensic genetics. Therefore, methods that allow the rapid, inexpensive and accurate sequencing of mtDNA are of great interest. One such method is the Affymetrix GeneChip® Human Mitochondrial Resequencing Array 2.0 (MitoChip v.2.0) (Santa Clara, CA). A direct comparison of 93 worldwide mitochondrial genomes sequenced by both the MitoChip and dideoxy terminator sequencing revealed an average call rate of 99.48% and an accuracy of ,99.98% for the MitoChip. The good performance was achieved by using in-house software for the automated analysis of additional probes on the array that cover the most common haplotypes in the hypervariable regions (HVR). Failure to call a base was associated mostly with the presence of either a run of ,4,C bases or a sequence variant within 12 bases up- or downstream of that base. A major drawback of the MitoChip is its inability to detect insertions/deletions and its low sensitivity and specificity in the detection of heteroplasmy. However, the vast majority of haplogroup defining polymorphism in the mtDNA phylogeny could be called unambiguously and more rapidly than with conventional sequencing. Hum Mutat 0,1,8, 2008. © 2008 Wiley-Liss, Inc. [source] Chromosomal anomalies on 6p25 in iris hypoplasia and Axenfeld-Rieger syndrome patients defined on a purpose-built genomic microarray,HUMAN MUTATION, Issue 1 2004Rosemary Ekong Abstract In many inherited diseases, the same phenotype can be produced both by single-base changes and by large deletions, or in some cases by duplications. Routine high-throughput sequencing can now detect small mutations relatively easily in a diagnostic setting, but deletions and duplications in the 50,500-kb region remain a more difficult problem. We have explored the application of array-CGH to the detection of such changes on a set of 20 samples consisting of patients with eye diseases associated with changes on chromosome 6p25 together with unaffected individuals, as well as two samples from tuberous sclerosis 2 (TSC2)-affected patients. We developed a microarray consisting of degenerate oligonucleotide primer (DOP)-PCR products from 260 human genomic clones, including BACs, PACs, and cosmids. In a masked study, chromosome changes in patients with iris hypoplasia (duplication) and Axenfeld-Rieger syndrome (deletion) were unequivocally distinguished from controls. Of the 20 6p25 samples analyzed, 19 were analyzed correctly (10 duplication cases, two deletions, and seven normals), while one individual failed to give a result because of poor hybridization. The extent of the duplication or deletion estimated was similar to that obtained by independent and much more time-consuming FISH experiments. On the other hand, deletions in the two TSC2 -affected samples, previously mapped by DNA molecular combing, were not detected on the array, possibly due to the repeat content of that region. Excluding the 16p13 cosmids, consistent results were obtained from all other cosmid clones; the potential for producing affordable disease-specific diagnostic microarray as an adjunct to diagnosis is discussed. Hum Mutat 24:76,85, 2004. © 2004 Wiley-Liss, Inc. [source] Fatal malignant melanoma in a child with neurofibromatosis type 1INTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 9 2007Yousef Bin Amer MBBS Neurofibromatosis type 1 is an autosomal dominant disease and is considered one of the most commonly inherited diseases in humans. Malignant melanoma has been reported in up to 5% of patients with neurofibromatosis type 1. We report a young Saudi boy with neurofibromatosis type 1 who developed fatal metastatic malignant melanoma arising from giant melanocytic nevi within speckled lentiginous nevus (SLN). [source] Hematological features and molecular lesions of hemoglobin gene disorders in Taiwanese patientsINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 1p2 2010H.-J. LIN Summary Hemoglobin (Hb) gene disorders are one of the most common inherited diseases in Taiwan, which include ,-thalassemia, ,-thalassemia, and Hb variants. In this study, we collected and analyzed mutations found in 930 patients with Hb gene disorders except Hb Bart's Hydrops and ,-thalassemia major. The patients included 650 cases of ,-thalassemia, 225 cases of ,-thalassemia, 9 cases of ,-thalassemia combined with ,-thalassemia, and 46 cases of Hb variants or Hb variants combined with ,-thalassemia or ,-thalassemia. The most common type of ,0 -thalassemia and ,++ -thalassemia mutations in our study were the SEA type deletion and the ,3.7 deletion, respectively; the most common ,-thalassemia mutation was the IVS-2 nt 654 C,T mutation; and the most common Hb variant was the HbE. We compared the relationships between genotype and hematological phenotypes of various Hb gene disorders and found that different genotypes of ,0 -thalassemia have similar hematological features. In conclusion, the results of our study provide data of the complex interaction of thalassemias and Hb variants which might be useful for other researchers in this field. [source] Microcephalia with mandibular and dental dysplasia in adult Zmpste24-deficient miceJOURNAL OF ANATOMY, Issue 5 2008F. De Carlos Abstract ZMPSTE24 (also called FACE-1) is a zinc-metalloprotease involved in the post-translational processing of prelamin A to mature lamin A, a major component of the nuclear envelope. Mutations in the ZMPSTE24 gene or in that encoding its substrate prelamin A (LMNA) result in a series of human inherited diseases known collectively as laminopathies and showing regional or systemic manifestations (i.e. the Hutchinson,Gilford progeria syndrome). Typically, patients suffering some laminopathies show craniofacial or mandible anomalies, aberrant dentition or facial features characteristic of aged persons. To analyse whether Zmpste24,/, mice reproduce the cranial phenotype observed in humans due to mutations in ZMPSTE24 or LMNA, we conducted a craniometric study based on micro-computer tomography (µCT) images. Furthermore, using simple radiology, µCT, µCT-densitometry and scanning electron microscopy, we analysed the mandible and the teeth from Zmpste24,/, mice. Finally, the structure of the lower incisor was investigated using an H&E technique. The results demonstrate that Zmpste24,/, mice are microcephalic and show mandibular and dental dysplasia affecting only the mandible teeth. In all cases, the lower incisor of mice lacking Zmpste24 was smaller than in control animals, showed cylindrical morphology and a transverse fissure at the incisal edge, and the pulpal cavity was severely reduced. Structurally, the dental layers were normally arranged but cellular layers were disorganized. The inferior molars showed a reduced cusp size. Taken together, these data strongly suggest that Zmpste24,/, mice represent a good model to analyse the craniofacial and teeth malformations characteristic of lamin-related pathologies, and might contribute to a better understanding of the molecular events underlying these diseases. [source] Molecular tests for coat colours in horsesJOURNAL OF ANIMAL BREEDING AND GENETICS, Issue 6 2009Stefan Rieder Summary Colour phenotypes may have played a major role during early domestication events and initial selection among domestic animal species. As coat colours mostly follow a relatively simple mode of Mendelian inheritance, they have been among the first traits to be systematically analysed at the molecular level. As a result of the number of genetic tools developed during the past decade, horse coat colour tests have been designed and are now commercially available for some of the basic phenotypes. These tests enable breeders to verify segregation within particular pedigrees, to select specific colour phenotypes according to market demand or studbook policies and to avoid complex inherited diseases associated with some of the colour patterns. This paper reviews the relevance of the topic, describes all currently available tests for coat colours in horses and addresses also ongoing research in this field. [source] A canine linkage map: 39 linkage groupsJOURNAL OF ANIMAL BREEDING AND GENETICS, Issue 1 2001F. Lingaas A low resolution canine marker map is an important tool in the further advancements in genetic analysis of dog breeds and the control and reduction of the frequency of inherited diseases. This study presents a genetic linkage analysis with 39 linkage groups using 222 polymorphic canine markers based on typing in the International DogMap reference families, consisting of 129 Beagle and German Shepherd dogs. Of these 39 linkage groups, 14 have been assigned to canine chromosomes by fluorescence in-situ hybridization (FISH). These results are a further refinement on the first linkage groups from the International DogMap collaboration and represent a continuing collaboration. Eine Markerkarte des Hundes mit 39 Kopplungsgruppen Schwach auflösende Markerkarten des Genoms stellen wichtige Hilfsmittel für die genetische Charakterisierung von Hunderassen dar. Sie können für die Kontrolle und Eindämmung von Erbkrankheiten verwendet werden. Die Resultate der vorgestellten Studie basieren auf der genetischen Typisierung von Hundefamilien des Internationalen DogMap Konsortiums. Die Familien bestehen aus 129 Beagle und Deutschen Schäferhunden. Die Studie stellt eine Kopplungsanalyse mit 39 Kopplungsgruppen vor, die insgesamt 1216 cM des Hundegenoms abdecken. Die Markerkarte enthält 222 polymorphe Hundemarker von denen 18 Gene sind. Fünfundachtzig Marker sind in keiner anderen Markerkarte publiziert. Vierzehn Kopplungsgruppen konnten mittels FISH chromosomal zugewiesen werden. Unsere Resultate stellen eine weitere Verfeinerung der ersten Markerkarte des DogMap Projektes dar und sind Ausdruck einer kontinuierlichen internationalen Zusammenarbeit. [source] Is Atrial Fibrillation a Genetic Disease?JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 5 2005RAMON BRUGADA M.D. Atrial fibrillation remains one of the most challenging arrhythmias for the clinician and basic researcher. Different approaches have been undertaken to improve its understanding; from the development of animal models to the analysis of genetic backgrounds in individuals with familial and acquired forms of the disease. In the last few years, a large body of evidence has shown that alterations in ionic currents are involved in the disease. However, it has not been until recently, with the genetic link between mutations in proteins responsible for these ionic currents and the familial disease, that we have been given the final evidence that atrial fibrillation can also be primarily an ion channelopathy. Despite the limited prevalence of the inherited diseases, it has been shown before that the knowledge gained in their study will be helpful in dealing with the most common acquired forms of the disease. Therefore, as data keep unraveling, clinicians can expect that soon better therapeutic and preventive options for atrial fibrillation will emerge from basic science. [source] Preimplantation genetic diagnosis of Morquio diseasePRENATAL DIAGNOSIS, Issue 10 2008Wafa Qubbaj Abstract Objectives Morquio syndrome is an autosomal recessive disease and mutations in the N -acetylgalactosamine 6-sulfate sulfatase (GALNS) gene cause Morquio type A disease. Preimplantation genetic diagnosis (PGD), an early form of prenatal diagnosis for couples at risk of transmitting inherited diseases, was applied to prevent transmission of this disease. Methods A couple with three affected children, having homozygous W159C (p. Trp 159 Cys) mutation in GALNS gene, underwent in vitro fertilization (IVF) treatment and PGD. Mutation analyses from the embryos were performed following whole genome amplification of single blastomeres using multiple displacement amplification (MDA). Results Three embryos were diagnosed as normal and two were transferred on day 4. The cycle resulted in a pregnancy and a live birth of a carrier male infant. Genetic haplotyping analysis of the infant and the leftover MDA samples enabled us to determine which embryo was implanted. The discrepancy in results was explained by allele dropout (ADO) of the mutant allele from the MDA product. Conclusions A feasible strategy for PGD of Morquio disease including whole genome amplification by MDA and the use of preimplantation genetic haplotyping is described. MDA product archiving will be useful for future investigations if needed. Copyright © 2008 John Wiley & Sons, Ltd. [source] | ||||||||||||||||