Nephrolithiasis, kidney failure and bone disorders in Dent disease patients with and without CLCN5 mutations

open9noDent disease (DD) is a rare X-linked recessive renal tubulopathy characterised by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis and/or nephrolithiasis. DD is caused by mutations in both the CLCN5 and OCRL genes. CLCN5 encodes the electrogenic chloride/proton exchanger ClC-5 which is involved in the tubular reabsorption of albumin and LMW proteins, OCRL encodes the inositol polyphosphate 5-phosphatase, and was initially associated with Lowe syndrome. In approximately 25 % of patients, no CLCN5 and OCRL mutations were detected. The aim of our study was to evaluate whether calcium phosphate metabolism disorders and their clinical complications are differently distributed among DD patients with and without CLCN5 mutations. Sixty-four male subjects were studied and classified into three groups: Group I (with CLCN5 mutations), Group II (without CLCN5 mutations) and Group III (family members with the same CLCN5 mutation). LMWP, hypercalciuria and phosphaturic tubulopathy and the consequent clinical complications nephrocalcinosis, nephrolithiasis, bone disorders, and chronic kidney disease (CKD) were considered present or absent in each patient. We found that the distribution of nephrolithiasis, bone disorders and CKD differs among patients with and without CLCN5 mutations. Only in patients harbouring CLCN5 mutations was age-independent nephrolithiasis associated with hypercalciuria, suggesting that nephrolithiasis is linked to altered proximal tubular function caused by a loss of ClC-5 function, in agreement with ClC-5 KO animal models. Similarly, only in patients harbouring CLCN5 mutations was age-independent kidney failure associated with nephrocalcinosis, suggesting that kidney failure is the consequence of a ClC-5 dysfunction, as in ClC-5 KO animal models. Bone disorders are a relevant feature of DD phenotype, as patients were mainly young males and this complication occurred independently of age. The triad of symptoms, LMWP, hypercalciuria, and nephrocalcinosis, was present in almost all patients with CLCN5 mutations but not in those without CLCN5 mutations. This lack of homogeneity of clinical manifestations suggests that the difference in phenotypes between the two groups might reflect different pathophysiological mechanisms, probably depending on the diverse genes involved. Overall, our results might suggest that in patients without CLCN5 mutations several genes instead of the prospected third DD underpin patients' phenotypes.openAnglani, Franca; D’Angelo, Angela; Bertizzolo, Luisa Maria; Tosetto, Enrica; Ceol, Monica; Cremasco, Daniela; Bonfante, Luciana; Addis, Maria Antonietta; Del Prete, DorellaAnglani, Franca; D'Angelo, Angela; Bertizzolo, Luisa Maria; Tosetto, Enrica; Ceol, Monica; Cremasco, Daniela; Bonfante, Luciana; Addis, Maria Antonietta; DEL PRETE, Dorell

Network based integrated analysis of phenotype-genotype data for prioritization of candidate symptom genes

YesSymptoms and signs (symptoms in brief) are the essential clinical manifestations for individualized diagnosis and treatment in traditional Chinese medicine (TCM). To gain insights into the molecular mechanism of symptoms, we develop a computational approach to identify the candidate genes of symptoms. This paper presents a network-based approach for the integrated analysis of multiple phenotype-genotype data sources and the prediction of the prioritizing genes for the associated symptoms. The method first calculates the similarities between symptoms and diseases based on the symptom-disease relationships retrieved from the PubMed bibliographic database. Then the disease-gene associations and protein-protein interactions are utilized to construct a phenotype-genotype network. The PRINCE algorithm is finally used to rank the potential genes for the associated symptoms. The proposed method gets reliable gene rank list with AUC (area under curve) 0.616 in classification. Some novel genes like CALCA, ESR1, and MTHFR were predicted to be associated with headache symptoms, which are not recorded in the benchmark data set, but have been reported in recent published literatures. Our study demonstrated that by integrating phenotype-genotype relationships into a complex network framework it provides an effective approach to identify candidate genes of symptoms.NSFC Project (61105055, 81230086), China 973 Program (2014CB542903), The National Key Technology R&D Program (2013BAI02B01, 2013BAI13B04), the National S&T Major Special Project on Major New Drug Innovation (2012ZX09503-001-003), and the Fundamental Research Funds for the Central Universities

Emerging patterns of genetic overlap across autoimmune disorders.

Most of the recently identified autoimmunity loci are shared among multiple autoimmune diseases. The pattern of genetic association with autoimmune phenotypes varies, suggesting that certain subgroups of autoimmune diseases are likely to share etiological similarities and underlying mechanisms of disease. In this review, we summarize the major findings from recent studies that have sought to refine genotype-phenotype associations in autoimmune disease by identifying both shared and distinct autoimmunity loci. More specifically, we focus on information from recent genome-wide association studies of rheumatoid arthritis, ankylosing spondylitis, celiac disease, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes and inflammatory bowel disease. Additional work in this area is warranted given both the opportunity it provides to elucidate pathogenic mechanisms in autoimmunity and its potential to inform the development of improved diagnostic and therapeutic tools for this group on complex human disorders

Perspectives on the revised Ghent criteria for the diagnosis of Marfan syndrome

Three international nosologies have been proposed for the diagnosis of Marfan syndrome (MFS): the Berlin nosology in 1988; the Ghent nosology in 1996 (Ghent-1); and the revised Ghent nosology in 2010 (Ghent-2). We reviewed the literature and discussed the challenges and concepts of diagnosing MFS in adults. Ghent-1 proposed more stringent clinical criteria, which led to the confirmation of MFS in only 32%-53% of patients formerly diagnosed with MFS according to the Berlin nosology. Conversely, both the Ghent-1 and Ghent-2 nosologies diagnosed MFS, and both yielded similar frequencies of MFS in persons with a causative FBN1 mutation (90% for Ghent-1 versus 92% for Ghent-2) and in persons not having a causative FBN1 mutation (15% versus 13%). Quality criteria for diagnostic methods include objectivity, reliability, and validity. However, the nosology-based diagnosis of MFS lacks a diagnostic reference standard and, hence, quality criteria such as sensitivity, specificity, or accuracy cannot be assessed. Medical utility of diagnosis implies congruency with the historical criteria of MFS, as well as with information about the etiology, pathogenesis, diagnostic triggers, prognostic triggers, and potential complications of MFS. In addition, social and psychological utilities of diagnostic criteria include acceptance by patients, patient organizations, clinicians and scientists, practicability, costs, and the reduction of anxiety. Since the utility of a diagnosis or exclusion of MFS is context-dependent, prioritization of utilities is a strategic decision in the process of nosology development. Screening tests for MFS should be used to identify persons with MFS. To confirm the diagnosis of MFS, Ghent-1 and Ghent-2 perform similarly, but Ghent-2 is easier to use. To maximize the utility of the diagnostic criteria of MFS, a fair and transparent process of nosology development is essential

Integrative omics approaches provide biological and clinical insights : examples from mitochondrial diseases

High-throughput technologies for genomics, transcriptomics, proteomics, and metabolomics, and integrative analysis of these data, enable new, systems-level insights into disease pathogenesis. Mitochondrial diseases are an excellent target for hypothesis-generating omics approaches, as the disease group is mechanistically exceptionally complex. Although the genetic background in mitochondrial diseases is in either the nuclear or the mitochondrial genome, the typical downstream effect is dysfunction of the mitochondrial respiratory chain. However, the clinical manifestations show unprecedented variability, including either systemic or tissue-specific effects across multiple organ systems, with mild to severe symptoms, and occurring at any age. So far, the omics approaches have provided mechanistic understanding of tissue-specificity and potential treatment options for mitochondrial diseases, such as metabolome remodeling. However, no curative treatments exist, suggesting that novel approaches are needed. In this Review, we discuss omics approaches and discoveries with the potential to elucidate mechanisms of and therapies for mitochondrial diseases.Peer reviewe

DNetDB: The human disease network database based on dysfunctional regulation mechanism

Additional analysis and concepts explanation. This file contains 1) comparison of DNetDB and the results of differential expression analysis (DEA-) based method ; 2) comparison of DNetDB and traditional disease classification; 3) negative disease relationships and 4) DCp and DCe. (DOCX 6926 kb

Utility of mass spectrometry for the diagnosis of the unstable coronary plaque.

Mass spectrometry is a powerful technique that is used to identify unknown compounds, to quantify known materials, and to elucidate the structure and chemical properties of molecules. Recent advances in the accuracy and speed of the technology have allowed data acquisition for the global analysis of lipids from complex samples such as blood plasma or serum. Here, mass spectrometry as a tool is described, its limitations explained and its application to biomarker discovery in coronary artery disease is considered. In particular an application of mass spectrometry for the discovery of lipid biomarkers that may indicate plaque morphology that could lead to myocardial infarction is elucidated