Increasing cholesterol synthesis in 7-dehydrosterol reductase (DHCR7) deficient mouse models through gene transfer. 2010

Xavier Matabosch, and Lee Ying, and Montserrat Serra, and Christopher A Wassif, and Forbes D Porter, and Cedric Shackleton, and Gordon Watson
Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609, United States.

Smith-Lemli-Opitz syndrome (SLOS) is caused by deficiency in the terminal step of cholesterol biosynthesis: the conversion of 7-dehydrocholesterol (7DHC) to cholesterol (C), catalyzed by 7-dehydrocholesterol reductase (DHCR7). This disorder exhibits several phenotypic traits including dysmorphia and mental retardation with a broad range of severity. There are few proven treatment options. That most commonly used is a high cholesterol diet that seems to enhance the quality of life and improve behavioral characteristics of patients, although these positive effects are controversial. The goal of our study was to investigate the possibility of restoring DHCR7 activity by gene transfer. We constructed an adeno-associated virus (AAV) vector containing the DHCR7 gene. After we infused this vector into affected mice, the introduced DHCR7 gene could be identified in liver, mRNA was expressed and a functional enzyme was produced. Evidence of functionality came from the ability to partially normalize the serum ratio of 7DHC/C in treated animals, apparently by increasing cholesterol production with concomitant decrease in 7DHC precursor. By 5 weeks after treatment the mean ratio (for 7 animals) had fallen to 0.05 while the ratio for untreated littermate controls had risen to 0.14. This provides proof of principle that gene transfer can ameliorate the genetic defect causing SLOS and provides a new experimental tool for studying the pathogenesis of this disease. If effective in humans, it might also offer a possible alternative to exogenous cholesterol therapy. However, it would not offer a complete cure for the disorder as many of the negative implications of defective synthesis are already established during prenatal development.

UI MeSH Term Description Entries
D002784 Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Epicholesterol
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D005822 Genetic Vectors DNA molecules capable of autonomous replication within a host cell and into which other DNA sequences can be inserted and thus amplified. Many are derived from PLASMIDS; BACTERIOPHAGES; or VIRUSES. They are used for transporting foreign genes into recipient cells. Genetic vectors possess a functional replicator site and contain GENETIC MARKERS to facilitate their selective recognition. Cloning Vectors,Shuttle Vectors,Vectors, Genetic,Cloning Vector,Genetic Vector,Shuttle Vector,Vector, Cloning,Vector, Genetic,Vector, Shuttle,Vectors, Cloning,Vectors, Shuttle
D000229 Dependovirus A genus of the family PARVOVIRIDAE, subfamily PARVOVIRINAE, which are dependent on a coinfection with helper adenoviruses or herpesviruses for their efficient replication. The type species is Adeno-associated virus 2. Adeno-Associated Viruses,Dependoparvovirus,Adeno-Associated Virus,Virus, Adeno-Associated,Viruses, Adeno-Associated,Adeno Associated Virus,Adeno Associated Viruses,Dependoparvoviruses,Dependoviruses,Virus, Adeno Associated,Viruses, Adeno Associated
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D044925 Oxidoreductases Acting on CH-CH Group Donors A subclass of enzymes which includes all dehydrogenases acting on carbon-carbon bonds. This enzyme group includes all the enzymes that introduce double bonds into substrates by direct dehydrogenation of carbon-carbon single bonds. Oxidoreductases Acting on CH CH Group Donors
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D018014 Gene Transfer Techniques The introduction of functional (usually cloned) GENES into cells. A variety of techniques and naturally occurring processes are used for the gene transfer such as cell hybridization, LIPOSOMES or microcell-mediated gene transfer, ELECTROPORATION, chromosome-mediated gene transfer, TRANSFECTION, and GENETIC TRANSDUCTION. Gene transfer may result in genetically transformed cells and individual organisms. Gene Delivery Systems,Gene Transfer Technique,Transgenesis,Delivery System, Gene,Delivery Systems, Gene,Gene Delivery System,Technique, Gene Transfer,Techniques, Gene Transfer,Transfer Technique, Gene,Transfer Techniques, Gene
D019082 Smith-Lemli-Opitz Syndrome An autosomal recessive disorder of CHOLESTEROL metabolism. It is caused by a deficiency of 7-dehydrocholesterol reductase, the enzyme that converts 7-dehydrocholesterol to cholesterol, leading to an abnormally low plasma cholesterol. This syndrome is characterized by multiple CONGENITAL ABNORMALITIES, growth deficiency, and INTELLECTUAL DISABILITY. 7-Dehydrocholesterol Reductase Deficiency,Hyperotosis Corticalis Generalisata Familiaris,Lethal Acrodysgenital Syndrome,Polydactyly, Sex Reversal, Renal Hypoplasia, And Unilobar Lung,RSH Syndrome,RSH-SLO Syndrome,Rutledge Friedman Harrod Syndrome,Rutledge Lethal Multiple Congenital Anomaly Syndrome,SLO Syndrome,Smith Lemli Opitz syndrome, type 1,Smith-Lemli-Opitz Syndrome, Type 1,Smith-Lemli-Opitz Syndrome, Type 2,Smith-Lemli-Opitz Syndrome, Type I,Smith-Lemli-Opitz Syndrome, Type II,7-Dehydrocholesterol Reductase Deficiencies,Acrodysgenital Syndrome, Lethal,Acrodysgenital Syndromes, Lethal,Deficiencies, 7-Dehydrocholesterol Reductase,Deficiency, 7-Dehydrocholesterol Reductase,Lethal Acrodysgenital Syndromes,RSH SLO Syndrome,RSH Syndromes,RSH-SLO Syndromes,Reductase Deficiencies, 7-Dehydrocholesterol,Reductase Deficiency, 7-Dehydrocholesterol,SLO Syndromes,Smith Lemli Opitz Syndrome,Smith Lemli Opitz Syndrome, Type 2,Smith Lemli Opitz Syndrome, Type I,Smith Lemli Opitz Syndrome, Type II,Syndrome, Lethal Acrodysgenital,Syndrome, RSH,Syndrome, SLO,Syndromes, RSH,Syndromes, SLO

Related Publications

Xavier Matabosch, and Lee Ying, and Montserrat Serra, and Christopher A Wassif, and Forbes D Porter, and Cedric Shackleton, and Gordon Watson
January 2017, The Journal of steroid biochemistry and molecular biology,
Xavier Matabosch, and Lee Ying, and Montserrat Serra, and Christopher A Wassif, and Forbes D Porter, and Cedric Shackleton, and Gordon Watson
October 2007, Steroids,
Xavier Matabosch, and Lee Ying, and Montserrat Serra, and Christopher A Wassif, and Forbes D Porter, and Cedric Shackleton, and Gordon Watson
October 2014, Biochimica et biophysica acta,
Xavier Matabosch, and Lee Ying, and Montserrat Serra, and Christopher A Wassif, and Forbes D Porter, and Cedric Shackleton, and Gordon Watson
January 2004, Steroids,
Xavier Matabosch, and Lee Ying, and Montserrat Serra, and Christopher A Wassif, and Forbes D Porter, and Cedric Shackleton, and Gordon Watson
June 2024, Biochemical and biophysical research communications,
Xavier Matabosch, and Lee Ying, and Montserrat Serra, and Christopher A Wassif, and Forbes D Porter, and Cedric Shackleton, and Gordon Watson
September 1953, The Biochemical journal,
Xavier Matabosch, and Lee Ying, and Montserrat Serra, and Christopher A Wassif, and Forbes D Porter, and Cedric Shackleton, and Gordon Watson
September 1987, Biochemical and biophysical research communications,
Xavier Matabosch, and Lee Ying, and Montserrat Serra, and Christopher A Wassif, and Forbes D Porter, and Cedric Shackleton, and Gordon Watson
May 1994, Genomics,
Xavier Matabosch, and Lee Ying, and Montserrat Serra, and Christopher A Wassif, and Forbes D Porter, and Cedric Shackleton, and Gordon Watson
April 2016, The Journal of biological chemistry,
Xavier Matabosch, and Lee Ying, and Montserrat Serra, and Christopher A Wassif, and Forbes D Porter, and Cedric Shackleton, and Gordon Watson
April 2015, Journal of lipid research,
Copied contents to your clipboard!