Abstract:
:Infantile neuronal ceroid lipofuscinosis (INCL, Infantile Batten disease) is an invariably fatal neurodegenerative pediatric disorder caused by an inherited mutation in the PPT1 gene. Patients with INCL lack the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1, EC 3.1.2.22), resulting in intracellular accumulation of autofluorescent storage material and subsequent neuropathology. The Ppt1(-/-) mouse is deficient in PPT1 activity and represents a useful animal model of INCL that recapitulates most of the clinical and pathological aspects of the disease. Preclinical therapeutic experiments performed in the INCL mouse include CNS-directed gene therapy and recombinant enzyme replacement therapy; both seek to re-establish therapeutic levels of the deficient enzyme. We present a novel method for the histochemical localization of PPT1 activity in the Ppt1(-/-) mouse. By utilizing the substrate CUS-9235, tissues known to be positive for PPT1 activity turn varying intensities of blue. Presented here are histochemistry data showing the staining pattern in Ppt1(-/-), wild type, and Ppt1(-/-) mice treated with enzyme replacement therapy or AAV2/9-PPT1-mediated gene therapy. Results are paired with quantitative biochemistry data that confirm the ability of CUS-9235 to detect and localize PPT1 activity. This new method complements the current tools for the study of INCL and evaluation of effective therapies.
journal_name
Mol Genet Metabjournal_title
Molecular genetics and metabolismauthors
Dearborn JT,Ramachandran S,Shyng C,Lu JY,Thornton J,Hofmann SL,Sands MSdoi
10.1016/j.ymgme.2015.11.004subject
Has Abstractpub_date
2016-02-01 00:00:00pages
210-6issue
2eissn
1096-7192issn
1096-7206pii
S1096-7192(15)30074-3journal_volume
117pub_type
杂志文章abstract::Lung dysfunction is an important part of the pathology of the neurodegenerative disorder, Niemann-Pick C1 (NPC1). We have studied the pulmonary disease in the Npc1(NIH/NIH) mouse model. On histology, we find large numbers of alveolar foamy macrophages but no alveolar proteinosis. Lung weight as percent of body weight ...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2011.03.001
更新日期:2011-06-01 00:00:00
abstract::Enzyme replacement therapy (ERT) with intravenous recombinant human alpha-l-iduronidase (IV rhIDU) is a treatment for patients with mucopolysaccharidosis I (MPS I). Spinal cord compression develops in MPS I patients due in part to dural and leptomeningeal thickening from accumulated glycosaminoglycans (GAG). We tested...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2010.06.020
更新日期:2010-10-01 00:00:00
abstract::Hereditary renal hypouricemia (HRH) is an inborn error of renal membrane transport specific for uric acid, resulting in increased renal urate clearance associated with hypouricemia. Apparently in most HRH patients, the disorder is caused by loss of function mutations in the gene SLC22A12 coding for human urate transpo...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章,评审
doi:10.1016/j.ymgme.2006.03.015
更新日期:2006-09-01 00:00:00
abstract::Phenylketonuria (PKU) is an autosomal recessive genetic disorder in which mutations in the phenylalanine-4-hydroxylase (PAH) gene result in an inactive enzyme (PAH, EC 1.14.16.1). The effect is an inability to metabolize phenylalanine (Phe), translating into elevated levels of Phe in the bloodstream (hyperphenylalanin...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章,评审
doi:10.1016/j.ymgme.2005.06.016
更新日期:2005-12-01 00:00:00
abstract::Glycogen storage disease type Ia (GSD-Ia) is caused by deleterious mutations in the glucose-6-phosphatase gene (G6PC). A molecular study of this gene was carried out in 11 Argentinean patients from 8 unrelated families. Four missense (p.Gln54Pro, p.Arg83Cys, p.Thr16Arg, and p.Tyr209Cys) and one deletion (c.79delC) mut...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2004.06.010
更新日期:2004-11-01 00:00:00
abstract:BACKGROUND:There appears little consensus concerning protein requirements in phenylketonuria (PKU). METHODS:A questionnaire completed by 63 European and Turkish IMD centres from 18 countries collected data on prescribed total protein intake (natural/intact protein and phenylalanine-free protein substitute [PS]) by age...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2015.03.006
更新日期:2015-05-01 00:00:00
abstract::Recently, our group and others cloned the TRMA disease gene, SLC19A2, which encodes a thiamin transporter. Here, we report the cloning and characterization of the full-length cDNA and genomic sequences of mouse Slc19a2. The Slc19a2 cDNA contained a 1494-bp open-reading frame, and had 5'- and 3'-untranslated regions of...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1006/mgme.2001.3184
更新日期:2001-06-01 00:00:00
abstract:BACKGROUND:Miller syndrome (post-axial acrofacial dysostosis) arises from gene mutations for the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). Nonetheless, despite demonstrated loss of enzyme activity dihydroorotate (DHO) has not been shown to accumulate, but paradoxically urine orotate has been reported t...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2016.06.008
更新日期:2016-09-01 00:00:00
abstract::In the present work we evaluated a variety of indicators of oxidative stress in distinct brain regions (striatum, cerebral cortex and hippocampus), the liver, and heart of 30-day-old glutaryl-CoA dehydrogenase deficient (Gcdh(-/-)) mice. The parameters evaluated included thiobarbituric acid-reactive substances (TBA-RS...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2012.03.002
更新日期:2012-05-01 00:00:00
abstract::A six-day-old girl was referred for severe hepatic failure, dehydratation, axial hypotonia, and both lactic acidosis and ketoacidosis. Biotin-unresponsive pyruvate carboxylase deficiency type B was diagnosed. Triheptanoin, an odd-carbon triglyceride, was administrated as a source for acetyl-CoA and anaplerotic propion...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2004.09.007
更新日期:2005-04-01 00:00:00
abstract::Cystic Fibrosis (CF) is an autosomal recessive disorder affecting 1/2000-4000 newborns in Caucasian populations. This lethal disease mainly affects respiratory and digestive organs as well as fertility in man. So far, the CF prevalence and mutational spectrum have showed specificity among populations and regions, maki...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2005.12.001
更新日期:2006-04-01 00:00:00
abstract::Human reproductive function is regulated mainly by luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Mutations of the human LH/ chorionic gonadotropin receptor (LHR) and the FSH receptor (FSHR) leading to either constitutive activation or inactivation of the receptors have been identified. All activatin...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章,评审
doi:10.1006/mgme.1997.2650
更新日期:1998-02-01 00:00:00
abstract::The Wnt pathway has been shown to play an important role in maintenance of stem cells and cell fate decisions in embryonic and adult stem cell populations. Activation of the Wnt pathway in mesenchymal stem cells and 3 T3-L1 cells inhibits adipogenesis and can lead to osteoblastogenesis. To evaluate the role of the Wnt...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2011.11.197
更新日期:2012-03-01 00:00:00
abstract::MPS IIIA is a lysosomal storage disorder caused by mutations in the sulphamidase gene, resulting in the accumulation of heparan sulphate glycosaminoglycans (HS GAGs). Symptoms predominantly manifest in the CNS and there is no current therapy that effectively addresses neuropathology in MPS IIIA patients. Recent studie...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2010.06.008
更新日期:2010-10-01 00:00:00
abstract::The Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare neurological disease characterized by ponto-bulbar palsy, bilateral sensorineural deafness, and respiratory insufficiency. Recent genetic studies have identified mutations in the C20orf54 gene, which encodes the human riboflavin (RF) transporter -2 (hRFT-2) and s...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2011.12.021
更新日期:2012-04-01 00:00:00
abstract::Hypotonia-cystinuria syndrome (HCS) is an autosomal recessive disorder caused by combined deletions of SLC3A1 and PREPL. Clinical features include cystinuria, neonatal hypotonia with spontaneous improvement, poor feeding in neonates, hyperphagia in childhood, growth hormone deficiency, and variable cognitive problems....
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2012.06.011
更新日期:2012-11-01 00:00:00
abstract::The mitochondrial 13513G>A (D393N) mutation in the ND5 subunit of the respiratory chain complex I was initially described in association with MELAS syndrome. Recent observations have linked this mutation to Leigh disease. We screened for the 13513G>A mutation in a cohort of 265 patients with Leigh and Leigh-like disea...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2008.04.004
更新日期:2008-08-01 00:00:00
abstract::Among the numerous congenital disorders of glycosylation concerning glycoproteins, only a single mutation in ganglioside biosynthesis had been reported until a few years ago: one in the ST3GAL5 gene, encoding GM3 synthase. More recently, additional mutations in the same gene were reported, together with several distin...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章,评审
doi:10.1016/j.ymgme.2018.06.014
更新日期:2018-08-01 00:00:00
abstract::Niemann-Pick disease type C (NP-C) is an autosomal recessive neurovisceral storage disease with neurodegeneration caused by mutations in either the NPC-1 or NPC-2 gene. The murine ortholog of NPC-1 is mutated in BALB/c npc(nih) and this mutant mouse shows equally conspicuous neurodegeneration and loss of neurons. Howe...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2004.08.017
更新日期:2005-01-01 00:00:00
abstract::For a population-based newborn screening program, challenges exist in using technological advances to improve the quality and efficiency of the existing screening program and to develop new diagnostic capabilities. A newly developed genotyping method for screening of common mutations within the beta-globin gene is des...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2003.12.007
更新日期:2004-03-01 00:00:00
abstract:BACKGROUND:There is current expansion of newborn screening (NBS) programs to include lysosomal storage disorders because of the availability of treatments that produce an optimal clinical outcome when started early in life. OBJECTIVE:To evaluate the performance of a multiplex-tandem mass spectrometry (MS/MS) enzymatic...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2016.05.015
更新日期:2016-08-01 00:00:00
abstract::The hph-1 ENU-mutant mouse provides a model of tetrahydrobiopterin deficiency for studying hyperphenylalaninaemia, dopa-response dystonia, and vascular dysfunction. We have successively localized the hph-1 mutation to a congenic interval of 1.6-2.8 Mb, containing the GCH gene encoding GTP cyclohydrolase I (GTP-CH I). ...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2004.04.006
更新日期:2004-07-01 00:00:00
abstract::Suppression therapy utilizes compounds that suppress translation termination at in-frame premature termination codons (PTCs) to restore full-length, functional protein. This approach may provide a treatment for diseases caused by nonsense mutations such as mucopolysaccharidosis type I-Hurler (MPS I-H). MPS I-H is a ly...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2011.10.005
更新日期:2012-01-01 00:00:00
abstract:BACKGROUND:Treatment of Fabry disease (FD) with recombinant alpha-galactosidase A (r-αGAL A) is complicated by the formation of anti-drug antibodies in the majority of male patients with the classical disease phenotype. Detailed information regarding antibody subtypes, onset and persistence of antibody development and ...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2018.11.008
更新日期:2019-02-01 00:00:00
abstract::Gaucher disease is caused by the defective catabolism of the simple glycosphingolipid, glucosylceramide (GlcCer), due to mutations in the GBA1 gene which encodes for acid β-glucosidase (GCase), the lysosomal enzyme that degrades GlcCer. Today, Gaucher disease patients are routinely treated with recombinant GCase, in a...
journal_title:Molecular genetics and metabolism
pub_type: 传,历史文章,杂志文章,评审
doi:10.1016/j.ymgme.2016.11.390
更新日期:2017-01-01 00:00:00
abstract::The aim of this study was to investigate the genetic background of familial clustering of diabetes using genome-wide linkage analysis combined with exome sequencing. We recruited a Japanese family with a 3-generation history of diabetes. The family comprised 16 members, 13 having been diagnosed with diabetes. Nine mem...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2013.02.010
更新日期:2013-05-01 00:00:00
abstract::The deficiency of a lysosomal enzyme, aspartylglucosaminidase, results in a lysosomal storage disorder, aspartylglucosaminuria, manifesting as progressive mental retardation. To understand tissue pathogenesis and disease progression we analyzed the developmental expression of the enzyme, especially in brain, which is ...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1006/mgme.1999.2872
更新日期:1999-08-01 00:00:00
abstract::Since the 1950s, scientists have attempted to characterize the relationship between diabetes mellitus (DM) and the hypothalamic-pituitary-adrenal (HPA) axis. Similar complications are seen in patients with diabetes and Cushing's syndrome, leading some to suggest that an underlying abnormality in the HPA axis may be re...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2010.09.012
更新日期:2010-12-01 00:00:00
abstract::Caenorhabditis elegans affords a model of primary mitochondrial dysfunction that provides insight into cellular adaptations which accompany mutations in nuclear genes that encode mitochondrial proteins. To this end, we characterized genome-wide expression profiles of C. elegans strains with mutations in nuclear-encode...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2007.11.007
更新日期:2008-04-01 00:00:00
abstract:INTRODUCTION:Alkaptonuria (AKU) is a rare inherited disorder of tyrosine metabolism resulting in an accumulation of homogentisic acid oxidation products in the joints and cardiovascular system. Aortic distensibility may be a non-invasive indicator of cardiovascular complications. Descending thoracic aortic distensibili...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2020.05.006
更新日期:2020-08-01 00:00:00