Aerobactin iron transport genes commonly encoded by certain ColV plasmids occur in the chromosome of a human invasive strain of Escherichia coli K1

The aerobactin-mediated iron uptake system encoded by pColV-K30 and other ColV plasmids has been associated with the ability of Escherichia coli strains to cause disease. We investigated whether the pColV-K30 aerobactin system is present in E. coli K1 VW187 isolated from a human neonate with meningitis. This strain exhibited a functional aerobactin-mediated iron uptake system, as assessed by a cross-feeding bioassay and by its sensitivity to cloacin, a bacteriocin that recognizes the outer membrane receptor for iron-aerobactin complexes. By using a variety of techniques, we could not find any plasmid harboring the aerobactin genes. Hybridization of restriction endonuclease-cleaved chromosomal DNA from strain VW187 with various clones containing subsets of the pColV-K30 aerobactin region showed that the aerobactin genes were located on a 10.5-kilobase-pair chromosomal HindIII restriction fragment which also contained IS1-like insertion sequences. The chromosomal aerobactin region showed a high degree of conservation when compared with the homologous region in plasmid pColV-K30, although it was located on a different restriction endonuclease site environment.

A Bayesian analysis of the chromosome architecture of human disorders by integrating reductionist data

In this paper, we present a Bayesian approach to estimate a chromosome and a disorder network from the Online Mendelian Inheritance in Man (OMIM) database. In contrast to other approaches, we obtain statistic rather than deterministic networks enabling a parametric control in the uncertainty of the underlying disorder-disease gene associations contained in the OMIM, on which the networks are based. From a structural investigation of the chromosome network, we identify three chromosome subgroups that reflect architectural differences in chromosome-disorder associations that are predictively exploitable for a functional analysis of diseases.

Liver abnormalities associated with celiac sprue. How common are they, what is their significance, and what do we do about them?

We prospectively measured serum alkaline phosphatase (ALP), aspartate and alanine transaminase (AST/ALT), and tested sera for antinuclear, smooth-muscle, and antimitochondrial antibodies (ANA, SMA, AMA) in our patients with celiac sprue to determine the prevalence of associated liver abnormalities and its relevance to clinical management. Of 129 patients, ALP was the only elevated enzyme in 12 (9%) and in most cases was not thought to reflect significant liver disease. Seventeen (13%) had elevated AST and/or ALT with normal ALP. Levels normalized in 15 patients after dietary gluten exclusion and remained elevated in 2 noncompliers. Two patients (2%) with elevated AST, ALT, and ALP underwent further investigation: one had negative autoantibodies, liver biopsy, and endoscopic retrograde cholangiography and the other had ANA-positive chronic active hepatitis; enzymes in both cases improved with a gluten-free diet. There was no significant association between elevated AST/ALT and positive ANA/SMA; no patient had AMA. Abnormalities in liver enzymes are common in celiac sprue, but usually respond to dietary gluten exclusion. We propose that there is no need for invasive liver investigation in these patients unless there is more specific evidence of primary liver disease or failure of dietary response.

Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (P(combined) = 4.09 × 10(-9); odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (P(combined) = 2.74 × 10(-10); OR = 1.14, 95% CI = 1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

Autosomal dominant Alport syndrome linked to the type IV collage alpha 3 and alpha 4 genes (COL4A3 and COL4A4)

Alport syndrome is a hereditary nephritis that may lead to end-stage renal disease (ESRD) in young adult life and is often associated with sensorineural deafness and/or ocular abnormalities. The majority of families are X-linked due to mutations in the COL4A5 gene at Xq22. Autosomal forms of the disease are also recognized with recessive disease, having been shown to be due to mutations in the COL4A3 and COL4A4 genes on chromosome 2. Familial benign haematuria has also been mapped to this region in some families.

Genetic renal abnormalities

Inherited disorders of renal structure and function are relatively common causes of end-stage renal disease requiring renal replacement therapy. A family history of haematuria, urinary tract infection or renal failure can alert the clinician to the possible diagnosis of underlying renal genetic abnormalities. In practice, the commonest inherited renal disorder is autosomal dominant polycystic kidney disease (ADPKD), characterized by multiple kidney cysts associated with hypertension and renal failure. Insights into the cell biology of ADPKD are informing new therapeutic approaches to limit cyst growth and prevent progressive renal failure. Non-visible haematuria is a clinical finding that presents a diagnostic challenge because it has so many possible causes. Mutations in the genes encoding collagen proteins within the glomerular basement membrane (GBM) can disrupt its normal barrier function. Thin basement membrane nephropathy, caused by GBM collagen gene mutations, is a relatively common cause of familial haematuria that normally has a good long-term prognosis. Alport syndrome is a rare and genetically heterogeneous condition leading to renal failure in men inheriting the X-linked gene defect. Single-gene defects may cause diverse renal tubular disorders, such as predisposition to renal calculi, diabetes insipidus, renal tubular acidosis or hypertension with associated electrolyte imbalance. Gene mutations responsible for familial renal cancer syndromes, such as tuberous sclerosis complex and von Hippel–Lindau disease, have also been identified

A genome-wide association study provides evidence for association of chromosome 8p23 (MYP10) and 10q21.1 (MYP15) with high myopia in the French population.

PURPOSE. Myopia is a complex trait affected by both genetic and environmental factors. High myopia is associated with increased risk of sight-threatening eye disorders such as retinal detachment. The purpose of this genome-wide association study was to identify susceptibility genes contributing to high myopia in the French population. METHODS. High myopic cases were genotyped using Affymetrix SNP 6.0 chips and population controls were selected from the GABRIEL French dataset in which samples were genotyped by Illumina Human610 quad array. The association study was conducted using 152,234 single nucleotide polymorphisms that were present on both manufacturers' chips in 192 high myopic cases and 1064 controls to identify associated regions. Imputation was performed on peak regions. RESULTS. Associations were found at known myopia locus MYP10 on chromosome 8p23 and MYP15 on chromosome 10q21.1. Rs189798 (8p23) and rs10825992 (10q21.1) showed the strongest associations in these regions (P=6.32x10-7 and P=2.17x10-5, respectively). The imputed results at 8p23 showed 2 peaks of interest. The first spanned 30kb including rs189798 between MIR4660 and PPP1R3B with the most significant association at rs17155227 (P=1.07x10-10). The second novel peak was 4kb in length, encompassing MIR124-1 and the MSRA gene, with the strongest association at rs55864141 (P=1.30x10-7). The peak of imputed data at 10q21.1 was 70kb in length between ZWINT and MIR3924, with rs3107503 having the lowest P value (P=1.54x10-7). CONCLUSION. We provide evidence for the association of MYP10 at 8p23 and MYP15 at 10p21.1 with high myopia in the French population and refine these regions of association.

Structural brain abnormalities in male schizophrenics reflect fronto-temporal dissociation

Background. Many studies have separately reported abnormalities of frontal and temporal lobe structures in schizophrenia, but little is known of structural fronto-temporal associations in this condition. We investigated whether male patients with chronic schizophrenia would show abnormal patterns of correlation between regional brain volumes.

Methods. Structural magnetic resonance images of the brain in 42 patients were compared with 43 matched unaffected controls. We explored the pattern of association between regional brain volumes by correlational analyses, and non-parametrically tested for significance of between-group differences by randomization.

Results. The schizophrenics demonstrated significant volume deficits in several brain regions (left temporal lobe and hippocampus, right dorsolateral prefrontal cortex), and significant volume increases in the ventricular system (third ventricle and left temporal horn of the lateral ventricle). Controls demonstrated large positive correlations (r > 0.4) between prefrontal and temporal lobe regions. By contrast, inter-regional correlations significantly reduced in schizophrenics included those between prefrontal, anterior cingulate and temporal regions, and between posterior cingulate and hippocampus (P < 0.05). The most salient abnormality in patients was a dissociation between prefrontal and superior temporal gyrus volumes (P < 0.01).

Conclusions. These results support the existence of a relative 'fronto-temporal dissociation' in schizophrenia which we suggest may be due to lack of mutually trophic influences during frontal and temporal lobe development.

Cooperativity of imprinted genes inactivated by acquired chromosome 20q deletions

Large regions of recurrent genomic loss are common in cancers; however, with a few well-characterized exceptions, how they contribute to tumor pathogenesis remains largely obscure. Here we identified primate-restricted imprinting of a gene cluster on chromosome 20 in the region commonly deleted in chronic myeloid malignancies. We showed that a single heterozygous 20q deletion consistently resulted in the complete loss of expression of the imprinted genes L3MBTL1 and SGK2, indicative of a pathogenetic role for loss of the active paternally inherited locus. Concomitant loss of both L3MBTL1 and SGK2 dysregulated erythropoiesis and megakaryopoiesis, 2 lineages commonly affected in chronic myeloid malignancies, with distinct consequences in each lineage. We demonstrated that L3MBTL1 and SGK2 collaborated in the transcriptional regulation of MYC by influencing different aspects of chromatin structure. L3MBTL1 is known to regulate nucleosomal compaction, and we here showed that SGK2 inactivated BRG1, a key ATP-dependent helicase within the SWI/SNF complex that regulates nucleosomal positioning. These results demonstrate a link between an imprinted gene cluster and malignancy, reveal a new pathogenetic mechanism associated with acquired regions of genomic loss, and underline the complex molecular and cellular consequences of "simple" cancer-associated chromosome deletions.

Dual-colour HER2/chromosome 17 chromogenic in situ hybridisation enables accurate assessment of HER2 genomic status in ovarian tumours

Ovarian cancer is a leading cause of gynaecological cancer-related morbidity and mortality. There has been increasing interest in the potential utility of anti-human epidermal growth factor receptor 2 (anti-HER2) agents in the treatment of this disease, with the attendant need to identify suitable predictive biomarkers of response to treatment.

Dual-colour HER2/chromosome 17 chromogenic in situ hybridisation assay enables accurate assessment of HER2 genomic status in gastric cancer and has potential utility in HER2 testing of biopsy samples

Determination of HER2 protein expression by immunohistochemistry (IHC) and genomic status by fluorescent in situ hybridisation (FISH) are important in identifying a subset of high HER2-expressing gastric cancers that might respond to trastuzumab. Although FISH is considered the standard for determination of HER2 genomic status, brightfield ISH is being increasingly recognised as a viable alternative. Also, the impact of HER2 protein expression/genomic heterogeneity on the accuracy of HER2 testing has not been well studied in the context of gastric biopsy samples.

Exclusion of linkage between schizophrenia and the D2 dopamine receptor gene region of chromosome 11q in 112 Irish multiplex families

A leading theory hypothesizes that schizophrenia arises from dysregulation of the dopamine system in certain brain regions. As this dysregulation could arise from abnormal expression of D2 dopamine receptors, the D2 receptor gene (DRD2) on chromosome 11q is a candidate locus for schizophrenia. We tested whether allelic variation at DRD2 and five surrounding loci cosegregated with schizophrenia in 112 small- to moderate-size Irish families containing two or more members affected with schizophrenia or schizoaffective disorder, defined by DSM-III-R. Evidence of linkage was assessed using varying definitions of illness and modes of transmission. Assuming genetic homogeneity, linkage between schizophrenia and large regions of 11q around DRD2 could be strongly excluded. Assuming genetic heterogeneity, variation at the DRD2 locus could be rejected as a major risk factor for schizophrenia in more than 50% of these families for all models tested and in as few as 25% of the families for certain models. The DRD2 linkage in fewer than 25% of these families could not be excluded under any of the models tested. Our results suggest that the major component of genetic susceptibility to schizophrenia is not due to allelic variation at the DRD2 locus or other genes in the surrounding chromosomal region.

A potential vulnerability locus for schizophrenia on chromosome 6p24-22:evidence for genetic heterogeneity

In 265 Irish pedigrees, with linkage analysis we find evidence for a vulnerability locus for schizophrenia in region 6p24-22. The greatest lod score, assuming locus heterogeneity, is 3.51 (P = 0.0002) with D6S296. Another test, the C test, also supported linkage, the strongest results being obtained with D6S296 (P = 0.00001), D6S274 (P = 0.004) and D6S285 (P = 0.006). Non-parametric analysis yielded suggestive, but substantially weaker, findings. This locus appears to influence the vulnerability to schizophrenia in roughly 15 to 30% of our pedigrees. Evidence for linkage was maximal using an intermediate phenotypic definition and declined when this definition was narrowed or was broadened to include other psychiatric disorders.

Evidence for a schizophrenia vulnerability locus on chromosome 8p in the Irish Study of High-Density Schizophrenia Families

This study was an attempt to replicate evidence for a vulnerability locus for schizophrenia and associated disorders in the 8p22-21 region reported by Pulver and colleagues.

No major schizophrenia locus detected on chromosome 1q in a large multicenter sample

Reports of substantial evidence for genetic linkage of schizophrenia to chromosome 1q were evaluated by genotyping 16 DNA markers across 107 centimorgans of this chromosome in a multicenter sample of 779 informative schizophrenia pedigrees. No significant evidence was observed for such linkage, nor for heterogeneity in allele sharing among the eight individual samples. Separate analyses of European-origin families, recessive models of inheritance, and families with larger numbers of affected cases also failed to produce significant evidence for linkage. If schizophrenia susceptibility genes are present on chromosome 1q, their population-wide genetic effects are likely to be small.