Abstract:
:Screening for mutations in the low density lipoprotein receptor (LDLR) gene has identified more than 1000 mutations as the cause of familial hypercholesterolemia (FH). In addition, numerous intronic mutations with uncertain effects on pre-mRNA splicing have also been identified. In this study, we have selected 18 intronic mutations in the LDLR gene for comprehensive studies of their effects on pre-mRNA splicing. Epstein-Barr virus (EBV) transformed lymphocytes from subjects heterozygous for these mutations were established and mRNA was studied by Northern blot analyses and reverse transcription polymerase chain reactions. Furthermore, functional studies of the LDLRs were performed by flow cytometry. The results of the wet-lab analyses were compared to the predictions obtained from bioinformatics analyses using the programs MaxEntScan, NetGene2 and NNSplice 0.9, which are commonly used software packages for prediction of abnormal splice sites. Thirteen of the 18 intronic mutations were found to affect pre-mRNA splicing in a biologically relevant way as determined by wet-lab analyses. Skipping of one or two exons was observed for eight of the mutations, intron inclusion was observed for four of the mutations and activation of a cryptic splice site was observed for two of the mutations. Transcripts from eight of the mutant alleles were subjected to degradation. The computational analyses of the normal and mutant splice sites, predicted abnormal splicing with a sensitivity of 100% and a specificity of 60%. Thus, bioinformatics analyses are valuable tools as a first screening of the effects of intronic mutations in the LDLR gene on pre-mRNA splicing.
journal_name
Mol Genet Metabjournal_title
Molecular genetics and metabolismauthors
Holla ØL,Nakken S,Mattingsdal M,Ranheim T,Berge KE,Defesche JC,Leren TPdoi
10.1016/j.ymgme.2008.12.014subject
Has Abstractpub_date
2009-04-01 00:00:00pages
245-52issue
4eissn
1096-7192issn
1096-7206pii
S1096-7192(08)00477-0journal_volume
96pub_type
杂志文章abstract::The mucopolysaccharidoses (MPS) are lysosomal storage disorders caused by defects in the enzymes involved in the degradation of glycosaminoglycans. Hurler syndrome (MPS I) and Sanfilippo syndrome (MPS III) are among the more common diseases in the group, each occurring with an incidence of approximately 1 in 100,000. ...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2011.02.011
更新日期:2011-06-01 00:00:00
abstract:OBJECTIVE:To better delineate the natural history of patients with methylmalonic aciduria (MMA). STUDY DESIGN:Thirty patients with vitamin-B12-unresponsive MMA (25 aged 1.5 to 22.0 years (y) at the end of the study and 5 who died during a metabolic crisis) were managed following standardized guidelines and studied ret...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2009.03.006
更新日期:2009-07-01 00:00:00
abstract::Resveratrol (RSV) is a small compound first identified as an activator of sirtuin 1 (SIRT1), a key factor in mediating the effects of caloric restriction. Since then, RSV received great attention for its widespread beneficial effects on health and in connection to many diseases. RSV improves the metabolism and the mit...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2018.10.004
更新日期:2019-01-01 00:00:00
abstract::Pompe disease is a rare, autosomal recessive disorder characterized by deficiency of lysosomal acid alpha-glucosidase and accumulation of lysosomal glycogen in many tissues. The variable clinical manifestations, broad phenotypic spectrum, and overlap of signs and symptoms with other neuromuscular diseases make diagnos...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2014.07.014
更新日期:2014-09-01 00:00:00
abstract::The disorder trimethylaminuria (TMAu) often manifests itself in a body odor for individuals affected. TMAu is due to decreased metabolism of dietary-derived trimethylamine (TMA). In a healthy individual, 95% or more of TMA is converted by the flavin-containing monooxygenase 3 (FMO3, EC 1.14.13.8) to non-odorous trimet...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2009.02.006
更新日期:2009-06-01 00:00:00
abstract::Most newborn screening (NBS) laboratories use second-tier molecular tests for cystic fibrosis (CF) using dried blood spots (DBS). The Centers for Disease Control and Prevention's NBS Quality Assurance Program offers proficiency testing (PT) in DBS for CF transmembrane conductance regulator (CFTR) gene mutation detecti...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2011.10.013
更新日期:2012-02-01 00:00:00
abstract::Maple syrup urine disease is an autosomal recessive disorder of branched-chain amino acids metabolism with a worldwide frequency of 1/185,000 live newborns. In Portugal, the incidence of the disease has not been assessed. Based on the review of the cases diagnosed by tandem mass spectrometry an incidence of 1/86,800 l...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2010.04.007
更新日期:2010-08-01 00:00:00
abstract::X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene that encodes a peroxisomal membrane located ABC half-transporter named ALDP. Mutations in ALDP result in elevated levels of very long-chain fatty acids (VLCFA) and reduced VLCFA beta-oxidation in peroxisomes. The peroxisomal membrane harbor...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章,评审
doi:10.1016/j.ymgme.2006.10.001
更新日期:2007-03-01 00:00:00
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journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1006/mgme.2000.3112
更新日期:2000-12-01 00:00:00
abstract:OBJECTIVE:To evaluate the efficacy and safety of dietary lysine restriction as an adjunct to pyridoxine therapy on biochemical parameters, seizure control, and developmental/cognitive outcomes in children with pyridoxine-dependent epilepsy (PDE) caused by antiquitin (ATQ) deficiency. METHODS:In this observational stud...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章,多中心研究
doi:10.1016/j.ymgme.2012.09.006
更新日期:2012-11-01 00:00:00
abstract::Ruminant placental lactogens (PLs) are structurally related to prolactins (PRLs) and growth hormones (GHs) and are secreted by placentae. Ruminant PLs are unusual in their capacity to bind and activate PRL and GH receptors (Rs) from other species. The present minireview summarizes several works showing that unlike in ...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章,评审
doi:10.1006/mgme.2002.3303
更新日期:2002-03-01 00:00:00
abstract::Mutations in the arylsulfatase E gene, located on the X chromosome, have been shown to cause chondrodysplasia punctata (CDP). A substitution of arginine with serine at amino acid 12 (R12S) was identified in a patient with typical features of mild symmetrical CDP including mild mental retardation. The proband was insti...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1006/mgme.1999.2935
更新日期:1999-12-01 00:00:00
abstract::Niemann-Pick type C (NP-C) is a rare recessive disorder associated with progressive supranuclear gaze palsy. Degeneration occurs initially for vertical saccades and later for horizontal saccades. There are studies of oculomotor degeneration in adult NP-C patients [1, 2] but no comparable studies in children. We used h...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2017.11.004
更新日期:2018-02-01 00:00:00
abstract::Mutated deoxyguanosine kinase (dGK), which catalyses the first step of the mitochondrial deoxypurine salvage pathway, accounts for a hepatocerebral variant of mitochondrial DNA (mtDNA) depletion syndromes. In order to elucidate the pathogenic mechanism of dGK deficiency, mitochondrial and cytoplasmic deoxyribonucleosi...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2008.07.007
更新日期:2008-11-01 00:00:00
abstract:PURPOSE:Hemophilia B, an X-linked disease, manifests with recurrent soft tissue bleeding episodes. Hermansky-Pudlak syndrome, a rare autosomal recessive disorder, is characterized by oculocutaneous albinism and an increased tendency to bleed due to a platelet storage pool defect. We report a novel mutation in HPS6 in a...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2016.08.009
更新日期:2016-11-01 00:00:00
abstract::Severe neurological deficits and mental retardation are frequently associated with disrupted ganglioside metabolism in a variety of gangliosidoses and lysosomal storage disorders. Accumulation of glycosphingolipids (GSLs) in the central nervous system (CNS) of humans and animals affected with several types of mucopoly...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1006/mgme.2000.3139
更新日期:2001-03-01 00:00:00
abstract::Early age at menarche is a risk factor for breast cancer. A previous study reported a significant positive association between the CYP3A4*1B variant allele and early puberty. We investigated whether polymorphisms of the CYP3A4, CYP17, CYP1B1, and CYP1A2 genes predict the age at onset of menarche. Five hundred eighty-t...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1006/mgme.2001.3260
更新日期:2001-12-01 00:00:00
abstract::Increased glucose metabolism through the hexosamine pathway may result in insulin resistance, impaired insulin secretion, and diabetic nephropathy. We hypothesized that variants of GFPT1 encoding glutamine-fructose-6-phosphate amidotransferase, the rate limiting enzyme in this pathway, could increase GFPT1 gene expres...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2004.05.004
更新日期:2004-08-01 00:00:00
abstract::Propionyl-CoA carboxylase (PCC, EC 6.4.1.3) is a mitochondrial, biotin-dependent enzyme that functions in the catabolism of branched-chain amino acids, fatty acids with odd-numbered chain lengths, and other metabolites. It catalyzes the ATP-dependent carboxylation of propionyl-CoA to d-methylmalonyl-CoA. PCC is compos...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1006/mgme.2001.3210
更新日期:2001-09-01 00:00:00
abstract::Gaucher disease is a prevalent lysosomal storage disease in which affected individuals inherit mutations in the gene (GBA1) encoding lysosomal acid β-glucosidase (glucocerebrosidase, GCase, EC 3.2.1.45). One of the most prevalent disease-causing mutations in humans is a N370S missense mutation in the GCase protein. As...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2012.04.018
更新日期:2012-07-01 00:00:00
abstract::Pompe Disease (PD) is a lysosomal storage disease caused by acid α-glucosidase deficiency. The infantile form typically results in death in the first year of life. Patient survival has improved with enzyme replacement therapy (ERT), but new complications are being recognized. We report three cases of infantile onset P...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2012.11.013
更新日期:2013-02-01 00:00:00
abstract::Mutant GBA was found recently to be the most prevalent risk factor for familial parkinsonism. The two diseases do not share common symptoms and there is no direct pathway to explain the mechanism by which GBA mutations can confer the risk. Increased burden on the degradative pathway caused by defective glucocerebrosid...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2010.08.004
更新日期:2010-12-01 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::A common variant (rs4712652) adjacent to the prolactin gene was recently associated with obesity using a genome-wide association study. The aim of this study was to replicate the association between rs4712652 and obesity and further examine if rs4712652 is associated with fat percentage and adiponectin levels in a pop...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2010.08.017
更新日期:2011-01-01 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: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::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::Mutations in DGUOK result in mitochondrial DNA (mtDNA) depletion and may present as neonatal liver failure. Neonatal hemochromatosis (NH(1)) is a liver disorder of uncertain and varied etiology characterized by hepatic and non-reticuloendothelial siderosis. To date, deoxyguanosine kinase (dGK(2)) deficiency has not be...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2011.03.006
更新日期:2011-07-01 00:00:00
abstract::Fish-odor syndrome or trimethylaminuria, is a rare inborn error of metabolism inherited in an autosomal recessive fashion, involving the dysfunction of hepatic enzyme flavin-containing monooxygenase 3 (FMO3) that converts fishy-smelling trimethylamine (TMA) into odorless trimethylamine-N-oxide (TMAO). This confers, to...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2006.02.014
更新日期:2006-06-01 00:00:00
abstract::DAX1 encoded by NR0B1, when mutated, is responsible for X-linked adrenal hypoplasia congenita (AHC). AHC is due to failure of the adrenal cortex to develop normally and is fatal if untreated. When duplicated, this gene is associated with an XY sex-reversed phenotype. DAX1 expression is present during development of th...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章,评审
doi:10.1016/j.ymgme.2003.08.023
更新日期:2003-09-01 00:00:00