Klein A.D.,Telethon Institute of Genetics and Medicine
Physiological Genomics | Year: 2017
The genetic basis of the phenotypic variability observed in patients can be studied in mice by generating disease models through genetic or chemical interventions in many genetic backgrounds where the clinical phenotypes can be assessed and used for genome-wide association studies (GWAS). This is particularly relevant for rare disorders, where patients sharing identical mutations can present with a wide variety of symptoms, but there are not enough number of patients to ensure statistical power of GWAS. Inbred strains are homozygous for each loci, and their single nucleotide polymorphisms catalogs are known and freely available, facilitating the bioinformatics and reducing the costs of the study, since it is not required to genotype every mouse. This kind of approach can be applied to pharmacogenomics studies as well. © 2017 The American Physiological Society.
Trapani I.,Telethon Institute of Genetics and Medicine |
Puppo A.,Telethon Institute of Genetics and Medicine |
Auricchio A.,Telethon Institute of Genetics and Medicine |
Auricchio A.,University of Naples Federico II
Progress in Retinal and Eye Research | Year: 2014
Inherited retinopathies (IR) are common untreatable blinding conditions. Most of them are inherited as monogenic disorders, due to mutations in genes expressed in retinal photoreceptors (PR) and in retinal pigment epithelium (RPE). The retina's compatibility with gene transfer has made transduction of different retinal cell layers in small and large animal models via viral and non-viral vectors possible. The ongoing identification of novel viruses as well as modifications of existing ones based either on rational design or directed evolution have generated vector variants with improved transduction properties. Dozens of promising proofs of concept have been obtained in IR animal models with both viral and non-viral vectors, and some of them have been relayed to clinical trials. To date, recombinant vectors based on the adeno-associated virus (AAV) represent the most promising tool for retinal gene therapy, given their ability to efficiently deliver therapeutic genes to both PR and RPE and their excellent safety and efficacy profiles in humans. However, AAVs' limited cargo capacity has prevented application of the viral vector to treatments requiring transfer of genes with a coding sequence larger than 5kb. Vectors with larger capacity, i.e. nanoparticles, adenoviral and lentiviral vectors are being exploited for gene transfer to the retina in animal models and, more recently, in humans. This review focuses on the available platforms for retinal gene therapy to fight inherited blindness, highlights their main strengths and examines the efforts to overcome some of their limitations. © 2014 Elsevier Ltd.
Nakano A.,University of Tokyo |
Nakano A.,RIKEN |
Luini A.,Telethon Institute of Genetics and Medicine
Current Opinion in Cell Biology | Year: 2010
There are, in theory, several ways in which proteins may pass through the Golgi apparatus. Among these, the cisternal progression-maturation mode has gained broad consensus. However, there remain questions regarding the molecular mechanisms by which resident proteins are sorted from cargo and move backward to the proximal cisterna in synchrony with cisternal progression. In this short review, we discuss current questions about the organisation of trafficking to, through, and out of the Golgi apparatus, as well as the main approaches being developed to address such questions in model organisms including yeast, mammals and plants. © 2010 Elsevier Ltd.
Sutterlin C.,University of California at Irvine |
Colanzi A.,Consorzio Mario Negri Sud |
Colanzi A.,Telethon Institute of Genetics and Medicine |
Colanzi A.,National Research Council Italy
Journal of Cell Biology | Year: 2010
The mammalian Golgi apparatus is characterized by a ribbon-like organization adjacent to the centrosome during interphase and extensive fragmentation and dispersal away from the centrosome during mitosis. It is not clear whether this dynamic association between the Golgi and centrosome is of functional significance. We discuss recent findings indicating that the Golgi-centrosome relationship may be important for directional protein transport and centrosome positioning, which are both required for cell polarization. We also summarize our current knowledge of the link between Golgi organization and cell cycle progression. © 2010 Sütterlin and Colanzi.
De Matteis M.A.,Telethon Institute of Genetics and Medicine |
Luini A.,Telethon Institute of Genetics and Medicine |
Luini A.,National Research Council Italy
New England Journal of Medicine | Year: 2011
It is reasonable to hope that our basic knowledge of membrane trafficking will continue to provide insights into the pathogenesis of mendelian diseases and that studies of these diseases will continue to enhance our understanding of the membrane- trafficking system. In particular, it will be of great interest in this context to learn how to place the genes that are involved in trafficking-related diseases into coherent pathogenetic pathways. Regrettably, the wealth of new insights into the molecular defects in membrane-trafficking disorders has not yet led to a proportionate availability availability of effective therapies. However, in the past few years, the potential of mendelian diseases to drive the process of drug development has been recognized. 52,53 An example in the field of membrane transport is cystic fibrosis. Effective modulators of the folding, trafficking, and activity of CFTR (the chloride channel that is mutated in cystic fibrosis35) have been found through high-throughput screening that was aimed at identifying pharmacologic treatments for this disease. Some of these modulators (e.g., VX-809) are now being tested in clinical trials.54 In addition, interest in the pathways affected in mendelian disorders is being raised further by the recognition that efforts to develop drugs for their treatment might also prove useful in common diseases in which the same pathways might have a pathogenetic role, such as type 2 diabetes and Alzheimer's disease. 52,53 Copyright © 2011 Massachusetts Medical Society. All rights reserved.
Venditti R.,Telethon Institute of Genetics and Medicine |
Wilson C.,Telethon Institute of Genetics and Medicine |
De Matteis M.A.,Telethon Institute of Genetics and Medicine
Trends in Cell Biology | Year: 2014
The vast majority of proteins that are transported to different cellular compartments and secreted from the cell require coat protein complex II (COPII) for export from the endoplasmic reticulum (ER). Many of the molecular mechanisms underlying COPII assembly are understood in great detail, but it is becoming increasingly evident that this basic machinery is insufficient to account for diverse aspects of protein export from the ER that are observed in vivo. Here we review recent data that have furthered our mechanistic understanding of COPII assembly and, in particular, how genetic diseases associated with the early secretory pathway have added fundamental insights into the regulation of ER-derived carrier formation. We also highlight some unresolved issues that future work should address to better understand the physiology of COPII-mediated transport. © 2013 Elsevier Ltd.
de Leo M.G.,Telethon Institute of Genetics and Medicine
Nature Cell Biology | Year: 2016
Phosphoinositides (PtdIns) control fundamental cell processes, and inherited defects of PtdIns kinases or phosphatases cause severe human diseases, including Lowe syndrome due to mutations in OCRL, which encodes a PtdIns(4,5)P2 5-phosphatase. Here we unveil a lysosomal response to the arrival of autophagosomal cargo in which OCRL plays a key part. We identify mitochondrial DNA and TLR9 as the cargo and the receptor that triggers and mediates, respectively, this response. This lysosome-cargo response is required to sustain the autophagic flux and involves a local increase in PtdIns(4,5)P2 that is confined in space and time by OCRL. Depleting or inhibiting OCRL leads to an accumulation of lysosomal PtdIns(4,5)P2, an inhibitor of the calcium channel mucolipin-1 that controls autophagosome–lysosome fusion. Hence, autophagosomes accumulate in OCRL-depleted cells and in the kidneys of Lowe syndrome patients. Importantly, boosting the activity of mucolipin-1 with selective agonists restores the autophagic flux in cells from Lowe syndrome patients. © 2016 Nature Publishing Group
Nigro V.,Telethon Institute of Genetics and Medicine |
Savarese M.,Telethon Institute of Genetics and Medicine
Acta Myologica | Year: 2014
Limb-girdle muscular dystrophies (LGMD) are a highly heterogeneous group of muscle disorders, which first affect the voluntary muscles of the hip and shoulder areas. The definition is highly descriptive and less ambiguous by exclusion: non-Xlinked, non-FSH, non-myotonic, non-distal, nonsyndromic, and non-congenital. At present, the genetic classification is becoming too complex, since the acronym LGMD has also been used for a number of other myopathic disorders with overlapping phenotypes. Today, the list of genes to be screened is too large for the gene-by-gene approach and it is well suited for targeted next generation sequencing (NGS) panels that should include any gene that has been so far associated with a clinical picture of LGMD. The present review has the aim of recapitulating the genetic basis of LGMD ordering and of proposing a nomenclature for the orphan forms. This is useful given the pace of new discoveries. Thity-one loci have been identified so far, eight autosomal dominant and 23 autosomal recessive. The dominant forms (LGMD1) are: LGMD1A (myotilin), LGMD1B (lamin A/C), LGMD1C (caveolin 3), LGMD1D (DNAJB6), LGMD1E (desmin), LGMD1F (transportin 3), LGMD1G (HNRPDL), LGMD1H (chr. 3). The autosomal recessive forms (LGMD2) are: LGMD2A (calpain 3), LGMD2B (dysferlin), LGMD2C (? sarcoglycan), LGMD2D (a sarcoglycan), LGMD2E (β sarcoglycan), LGMD2F (d sarcoglycan), LGMD2G (telethonin), LGMD2H (TRIM32), LGMD2I (FKRP), LGMD2J (titin), LGMD2K (POMT1), LGMD2L (anoctamin 5), LGMD2M (fukutin), LGMD2N (POMT2), LGMD2O (POMTnG1), LGMD2P (dystroglycan), LGMD2Q (plectin), LGMD2R (desmin), LGMD2S (TRAPPC11), LGMD2T (GMPPB), LGMD2U (ISPD), LGMD2V (Glucosidase, alpha ), LGMD2W (PINCH2).
De Matteis M.A.,Telethon Institute of Genetics and Medicine |
Rega L.R.,Bambino Gesu Childrens Hospital Scientific Institute
Current Opinion in Cell Biology | Year: 2015
Although they were identified as long ago as the 1960s, there are still many unknowns regarding the functions and composition of membrane contact sites between the endoplasmic reticulum (ER) and the trans-Golgi (TG). While it seems to be fairly well established that they facilitate lipid exchange between the two organelles, much less is known about how they are regulated. A bottleneck in the study of the ER-TG contact sites has been the absence of methods for their biochemical isolation and visualization by light microscopy. Herein we provide an overview of current knowledge about ER-TG contact sites with a particular emphasis on the questions that remain to be explored. © 2015.
Glick B.S.,University of Chicago |
Luini A.,Telethon Institute of Genetics and Medicine
Cold Spring Harbor Perspectives in Biology | Year: 2011
Avariety of secretory cargoes move through the Golgi, but the pathways and mechanisms of this traffic are still being debated. Here, we evaluate the strengths and weaknesses of five current models for Golgi traffic: (1) anterograde vesicular transport between stable compartments, (2) cisternal progression/maturation, (3) cisternal progression/maturation with heterotypic tubular transport, (4) rapid partitioning in a mixed Golgi, and (5) stable compartments as cisternal progenitors. Each model is assessed for its ability to explain a set of key observations encompassing multiple cell types. No single model can easily explain all of the observations from diverse organisms. However, we propose that cisternal progression/ maturation is the best candidate for a conserved core mechanism of Golgi traffic, and that some cells elaborate this core mechanism by means of heterotypic tubular transport between cisternae. © 2011 Cold Spring Harbor Laboratory Press.