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Abnormal glycosylation and altered Golgi structure in colorectal cancer: dependence on intra-Golgi pH.

https://arctichealth.org/en/permalink/ahliterature19175
Source
FEBS Lett. 2002 Apr 10;516(1-3):217-24
Publication Type
Article
Date
Apr-10-2002
Author
Sakari Kellokumpu
Raija Sormunen
Ilmo Kellokumpu
Author Affiliation
Department of Biochemistry, University of Oulu, P.O. Box 3000, FIN-90014, Oulu, Finland. sakari.kellokumpu@oulu.fi
Source
FEBS Lett. 2002 Apr 10;516(1-3):217-24
Date
Apr-10-2002
Language
English
Publication Type
Article
Keywords
Animals
Antigens, Tumor-Associated, Carbohydrate - metabolism
Breast Neoplasms - immunology - metabolism - ultrastructure
COS Cells
Cells, Cultured
Colorectal Neoplasms - immunology - metabolism - ultrastructure
Female
Glycosylation
Golgi Apparatus - immunology - metabolism - ultrastructure
Humans
Hydrogen-Ion Concentration
Ion Transport
Microscopy, Electron
Rats
Research Support, Non-U.S. Gov't
Tumor Cells, Cultured
Abstract
Abnormal glycosylation of cellular glycoconjugates is a common phenotypic change in many human tumors. Here, we explore the possibility that an altered Golgi pH may also be responsible for these cancer-associated glycosylation abnormalities. We show that a mere dissipation of the acidic Golgi pH results both in increased expression of some cancer-associated carbohydrate antigens and in structural disorganization of the Golgi apparatus in otherwise normally glycosylating cells. pH dependence of these alterations was confirmed by showing that an acidification-defective breast cancer cell line (MCF-7) also displayed a fragmented Golgi apparatus, whereas the Golgi apparatus was structurally normal in its acidification-competent subline (MCF-7/AdrR). Acidification competence was also found to rescue normal glycosylation potential in MCF-7/AdrR cells. Finally, we show that abnormal glycosylation is also accompanied by similar structural disorganization and fragmentation of the Golgi apparatus in colorectal cancer cells in vitro and in vivo. These results suggest that an inappropriate Golgi pH may indeed be responsible for the abnormal Golgi structure and lowered glycosylation potential of the Golgi apparatus in malignant cells.
PubMed ID
11959136 View in PubMed
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The basis of prostaglandin synthesis in coral: molecular cloning and expression of a cyclooxygenase from the Arctic soft coral Gersemia fruticosa.

https://arctichealth.org/en/permalink/ahliterature3964
Source
J Biol Chem. 2001 Mar 9;276(10):7033-40
Publication Type
Article
Date
Mar-9-2001
Author
R. Koljak
I. Järving
R. Kurg
W E Boeglin
K. Varvas
K. Valmsen
M. Ustav
A R Brash
N. Samel
Author Affiliation
Department of Bioorganic Chemistry, Institute of Chemistry, Tallinn Technical University, Akadeemia tee 15, Tallinn 12618, Estonia.
Source
J Biol Chem. 2001 Mar 9;276(10):7033-40
Date
Mar-9-2001
Language
English
Publication Type
Article
Keywords
Alanine - chemistry
Amino Acid Sequence
Animals
Arginine - chemistry
Blotting, Northern
COS Cells
Chromatography, Thin Layer
Cloning, Molecular
Cnidaria - metabolism
Cyclooxygenase 1
Cyclooxygenase 2
DNA, Complementary - metabolism
Hela Cells
Histidine - chemistry
Humans
Isoenzymes - chemistry
Isoleucine - chemistry
Membrane Proteins
Microscopy, Fluorescence
Models, Genetic
Molecular Sequence Data
Phylogeny
Plasmids - metabolism
Polymerase Chain Reaction
Prostaglandin-Endoperoxide Synthases - biosynthesis - chemistry - genetics
Prostaglandins - biosynthesis
Protein Binding
RNA, Messenger - metabolism
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Sequence Analysis, DNA
Sequence Homology, Amino Acid
Serine - chemistry
Tyrosine - chemistry
Abstract
In vertebrates, the synthesis of prostaglandin hormones is catalyzed by cyclooxygenase (COX)-1, a constitutively expressed enzyme with physiological functions, and COX-2, induced in inflammation and cancer. Prostaglandins have been detected in high concentrations in certain corals, and previous evidence suggested their biosynthesis through a lipoxygenase-allene oxide pathway. Here we describe the discovery of an ancestor of cyclooxygenases that is responsible for prostaglandin biosynthesis in coral. Using a homology-based polymerase chain reaction cloning strategy, the cDNA encoding a polypeptide with approximately 50% amino acid identity to both mammalian COX-1 and COX-2 was cloned and sequenced from the Arctic soft coral Gersemia fruticosa. Nearly all the amino acids essential for substrate binding and catalysis as determined in the mammalian enzymes are represented in coral COX: the arachidonate-binding Arg(120) and Tyr(355) are present, as are the heme-coordinating His(207) and His(388); the catalytic Tyr(385); and the target of aspirin attack, Ser(530). A key amino acid that determines the sensitivity to selective COX-2 inhibitors (Ile(523) in COX-1 and Val(523) in COX-2) is present in coral COX as isoleucine. The conserved Glu(524), implicated in the binding of certain COX inhibitors, is represented as alanine. Expression of the G. fruticosa cDNA afforded a functional cyclooxygenase that converted exogenous arachidonic acid to prostaglandins. The biosynthesis was inhibited by indomethacin, whereas the selective COX-2 inhibitor nimesulide was ineffective. We conclude that the cyclooxygenase occurs widely in the animal kingdom and that vertebrate COX-1 and COX-2 are evolutionary derivatives of the invertebrate precursor.
PubMed ID
11085996 View in PubMed
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BRCA1 and BRCA2 bind Stat5a and suppress its transcriptional activity.

https://arctichealth.org/en/permalink/ahliterature18760
Source
FEBS Lett. 2002 Dec 4;532(1-2):247-52
Publication Type
Article
Date
Dec-4-2002
Author
H. Vidarsson
E K Mikaelsdottir
T. Rafnar
D. Bertwistle
A. Ashworth
J E Eyfjord
S. Valgeirsdottir
Author Affiliation
Molecular and Cell Biology Research Laboratory, Icelandic Cancer Society, Reykjavik, Iceland.
Source
FEBS Lett. 2002 Dec 4;532(1-2):247-52
Date
Dec-4-2002
Language
English
Publication Type
Article
Keywords
Animals
BRCA1 Protein - metabolism
BRCA2 Protein - metabolism
Breast - cytology - metabolism
Breast Neoplasms - metabolism
COS Cells
Cell Line
DNA-Binding Proteins - antagonists & inhibitors - metabolism
Epithelial Cells - metabolism
Female
Milk Proteins
Precipitin Tests
Research Support, Non-U.S. Gov't
STAT5 Transcription Factor
Trans-Activation (Genetics)
Trans-Activators - antagonists & inhibitors - metabolism
Abstract
Germline mutations in the breast cancer susceptibility genes, BRCA1 and BRCA2, are thought to account for a large portion of familial breast cancer. The increased risk of breast cancer in women carrying such mutations suggests that these proteins play a critical role in the growth regulation of mammary epithelial cells. Another protein, Stat5a, is known to be essential for growth and terminal differentiation of breast epithelial cells. Here we show that Stat5a forms a complex with both BRCA1 and BRCA2 in breast epithelial cells upon stimulation with prolactin. In addition, we show that the activity of Stat5a on the beta-casein promoter is modulated by both BRCA1 and BRCA2. This interaction may be important during the expansion and terminal differentiation of breast epithelial cells, as happens during pregnancy and lactation.
PubMed ID
12459499 View in PubMed
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Defective acidification of intracellular organelles results in aberrant secretion of cathepsin D in cancer cells.

https://arctichealth.org/en/permalink/ahliterature17599
Source
J Biol Chem. 2004 Sep 17;279(38):39982-8
Publication Type
Article
Date
Sep-17-2004
Author
Nina Kokkonen
Antti Rivinoja
Annika Kauppila
Marko Suokas
Ilmo Kellokumpu
Sakari Kellokumpu
Author Affiliation
Department of Biochemistry, University of Oulu, P. O. Box 3000, FIN-90014 Oulu, Finland.
Source
J Biol Chem. 2004 Sep 17;279(38):39982-8
Date
Sep-17-2004
Language
English
Publication Type
Article
Keywords
Acids - metabolism
Ammonium Chloride - pharmacology
Animals
Antigens, CD - metabolism
Breast Neoplasms
COS Cells
Caco-2 Cells
Cathepsin D - metabolism - secretion
Diuretics - pharmacology
Endosomes - drug effects - metabolism
Golgi Apparatus - drug effects - metabolism
HT29 Cells
Humans
Lysosome-Associated Membrane Glycoproteins
Lysosomes - drug effects - metabolism
Research Support, Non-U.S. Gov't
Abstract
Aberrant secretion of lysosomal hydrolases such as (pro)cathepsin D (proCD) is a common phenotypic change in many human cancers. Here we explore the underlying molecular defect(s) and find that MCF-7 breast and CaCo-2 colorectal cancer cells that are unable to acidify their endosomal compartments secreted higher amounts of proCD than did acidification-competent cancer cell types. The latter secreted equivalent amounts of proCD only after dissipation of their organellar pH gradients with NH(4)Cl. Assessing the critical steps that resulted in proCD secretion revealed that the Golgi-associated sorting receptor for CD, i.e. the cation-independent mannose-6-phosphate receptor (MPR300), was aberrantly distributed in acidification-defective MCF-7 cells. It accumulated mainly in late endosomes and/or lysosomes as a complex with its ligand (proCD or intermediate CD), as evidenced by its co-localization with both CD and LAMP-2, a late endosome/lysosome marker. Our immunoprecipitation analyses also showed that MCF-7 cells possessed 7-fold higher levels of receptor-enzyme complexes than did acidification-competent cells. NH(4)Cl induced similar receptor redistribution into LAMP-2-positive structures in acidification-competent cells but not in MCF-7 cells. The receptor also recovered its normal Golgi localization upon drug removal. Based on these observations, we conclude that defective acidification results in the aberrant secretion of proCD in certain cancer cells and interferes mainly with the normal disassembly of the receptor-enzyme complexes and efficient receptor reutilization in the Golgi.
PubMed ID
15258139 View in PubMed
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Detection of a set of peptide vaccine candidates for use in HLA-A31+ epithelial cancer patients.

https://arctichealth.org/en/permalink/ahliterature3907
Source
Int J Oncol. 2004 Feb;24(2):337-47
Publication Type
Article
Date
Feb-2004
Author
Hiroko Takedatsu
Shigeki Shichijo
Kouichi Azuma
Hidetoshi Takedatsu
Michio Sata
Kyogo Itoh
Author Affiliation
Department of Immunology, Kurume University School of Medicine, Kurume, Japan.
Source
Int J Oncol. 2004 Feb;24(2):337-47
Date
Feb-2004
Language
English
Publication Type
Article
Keywords
Alleles
Amino Acid Sequence
Animals
Antigens, Neoplasm
Blotting, Northern
COS Cells
Cancer Vaccines - therapeutic use
Cell Line, Tumor
DNA, Complementary - metabolism
Dose-Response Relationship, Drug
Epitopes - chemistry
Epitopes, T-Lymphocyte
HLA-A Antigens - biosynthesis - genetics
Humans
Immunotherapy - methods
Leukocytes, Mononuclear - metabolism
Molecular Sequence Data
Neoplasms, Glandular and Epithelial - ethnology - genetics - metabolism
Peptides - chemistry
RNA, Messenger - metabolism
Research Support, Non-U.S. Gov't
Sequence Homology, Amino Acid
T-Lymphocytes, Cytotoxic - metabolism
Vaccines, Subunit - chemistry
Abstract
The molecular basis of host-tumor interaction in HLA-A31+ cancer patients has not been well understood. This lack of clarification is hampering the development of specific immunotherapies for these patients. This study aimed to identify a set of CTL-epitope peptides applicable for the specific immunotherapy of cancer patients with HLA-A31 allele. HLA-A31 allele is expressed in 5-10% of the world population, with the highest expression among Brazilian Amerinds (65%), and the lowest in the Eskimo population (0%). We report herein four cDNAs encoding CTL-epitopes and 7 epitope peptides with the ability to induce HLA-A31-restricted CTLs cytotoxic to tumor cell lines in the peripheral blood mononuclear cells of HLA-A31+ cancer patients. These peptides might be useful for the development of a peptide-based immunotherapy for HLA-A31+ cancer patients.
PubMed ID
14719110 View in PubMed
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Detection of PMS2 Mutations by Screening Hereditary Nonpolyposis Colon Cancer Families from Denmark and Sweden.

https://arctichealth.org/en/permalink/ahliterature310019
Source
Genet Test Mol Biomarkers. 2019 Sep; 23(9):688-695
Publication Type
Journal Article
Date
Sep-2019
Author
Henrik Okkels
Kristina Lagerstedt-Robinsson
Friedrik P Wikman
Thomas V O Hansen
Ihab Lolas
Lars Joachim Lindberg
Henrik B Krarup
Author Affiliation
Section of Molecular Diagnostics, Department of Clinical Chemistry, Aalborg University Hospital, Aalborg, Denmark.
Source
Genet Test Mol Biomarkers. 2019 Sep; 23(9):688-695
Date
Sep-2019
Language
English
Publication Type
Journal Article
Keywords
Animals
COS Cells
Chlorocebus aethiops
Colorectal Neoplasms - diagnosis - genetics
Colorectal Neoplasms, Hereditary Nonpolyposis - diagnosis - genetics
DNA Mutational Analysis
Denmark
Early Detection of Cancer
High-Throughput Nucleotide Sequencing
Mismatch Repair Endonuclease PMS2 - genetics
Multiplex Polymerase Chain Reaction
Polymerase Chain Reaction
Sweden
Abstract
Background and Aims: Hereditary nonpolyposis colon cancer (HNPCC) and Lynch syndrome (LS) are characterized by defects in the mismatch repair (MMR) system, which protects the integrity of the genome. Pathogenic variants in four MMR genes (MLH1, MSH2, MSH6, and PMS2) are responsible for LS, an autosomal, dominant hereditary disease that occurs with a frequency of 2-5% among all colorectal cancer cases. It has been estimated that ~2-5% of all pathogenic variants found in the four MMR genes in LS cases are detected in the PMS2 gene. An overview of detected variants is presented here. Materials and Methods: Long-range (LR) PMS2 polymerase chain reaction (PCR) and PMS2 multiplex ligation probe amplification (MLPA) assays were used to detect PMS2 variants in ~1500 probands. In a subset of the probands, pathogenic PMS2 variants were detected by next-generation sequencing, and all detected variants were confirmed by LR-PCR combined with an MLPA assay. Results: A summary of PMS2 mutation analyses performed on colon cancer patients from molecular diagnostic laboratories in Denmark and Sweden is presented. By screening ~1500 HNPCC probands, a total of 40 different PMS2 variants were detected in 71 probands (5%); 20 variants were classified as pathogenic (C5), 2 variants as likely pathogenic (C4), 15 variants as variants of unknown significance (VUSs) (C3), 1 variant as likely benign (C2), and 2 variants as benign (C1). In total, 22/71 (31%) of the probands carried a pathogenic sequence variant. Among the probands with isolated loss of pPMS2 expression, the fraction of pathogenic variants was 20/35 (55%). Conclusions: Approximately 5% of the probands found in the Danish and Swedish populations presented here carried a PMS2 variant. In this study, six novel pathogenic variants and seven VUSs are reported.
PubMed ID
31433215 View in PubMed
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Disruption of an exon splicing enhancer in exon 3 of MLH1 is the cause of HNPCC in a Quebec family.

https://arctichealth.org/en/permalink/ahliterature174535
Source
J Med Genet. 2006 Feb;43(2):153-6
Publication Type
Article
Date
Feb-2006
Author
S. McVety
L. Li
P H Gordon
G. Chong
W D Foulkes
Source
J Med Genet. 2006 Feb;43(2):153-6
Date
Feb-2006
Language
English
Publication Type
Article
Keywords
Adaptor Proteins, Signal Transducing
Animals
COS Cells
Carrier Proteins - genetics
Cercopithecus aethiops
Colorectal Neoplasms, Hereditary Nonpolyposis - genetics
Exons - genetics
Humans
Nuclear Proteins - genetics
Point Mutation - genetics
Quebec
RNA Splice Sites - genetics
RNA Splicing - genetics
Regulatory Sequences, Ribonucleic Acid - genetics
Abstract
A 3 bp deletion located at the 5' end of exon 3 of MLH1, resulting in deletion of exon 3 from RNA, was recently identified.
That this mutation disrupts an exon splicing enhancer (ESE) because it occurs in a purine-rich sequence previously identified as an ESE in other genes, and ESEs are often found in exons with splice signals that deviate from the consensus signals, as does the 3' splice signal in exon 3 of MLH1.
The 3 bp deletion and several other mutations were created by polymerase chain reaction mutagenesis and tested using an in vitro splicing assay. Both mutant and wild type exon 3 sequences were cloned into an exon trapping vector and transiently expressed in Cos-1 cells.
Analysis of the RNA indicates that the 3 bp deletion c.213_215delAGA (gi:28559089, NM_000249.2), a silent mutation c.216T-->C, a missense mutation c.214G-->C, and a nonsense mutation c.214G-->T all cause varying degrees of exon skipping, suggesting the presence of an ESE at the 5' end of exon 3. These mutations are situated in a GAAGAT sequence 3 bp downstream from the start of exon 3.
The results of the splicing assay suggest that inclusion of exon 3 in the mRNA is ESE dependent. The exon 3 ESE is not recognised by all available motif scoring matrices, highlighting the importance of RNA analysis in the detection of ESE disrupting mutations.
Notes
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PubMed ID
15923275 View in PubMed
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Elevated Golgi pH impairs terminal N-glycosylation by inducing mislocalization of Golgi glycosyltransferases.

https://arctichealth.org/en/permalink/ahliterature89702
Source
J Cell Physiol. 2009 Jul;220(1):144-54
Publication Type
Article
Date
Jul-2009
Author
Rivinoja Antti
Hassinen Antti
Kokkonen Nina
Kauppila Annika
Kellokumpu Sakari
Author Affiliation
Department of Biochemistry and The Finnish Glycoscience Graduate School, University of Oulu, Oulu, Finland.
Source
J Cell Physiol. 2009 Jul;220(1):144-54
Date
Jul-2009
Language
English
Publication Type
Article
Keywords
Animals
COS Cells
Carcinoembryonic Antigen - metabolism
Cercopithecus aethiops
Chloroquine - pharmacology
Dose-Response Relationship, Drug
Endosomes - enzymology
Galactosyltransferases - metabolism
Glycosylation
Glycosyltransferases - genetics - metabolism
Golgi Apparatus - drug effects - enzymology
Hydrogen-Ion Concentration
Lysosomes - enzymology
Mannosidases - metabolism
Mutation
Protein Processing, Post-Translational - drug effects
Protein Structure, Tertiary
Protein Transport
Recombinant Fusion Proteins - metabolism
Sialyltransferases - metabolism
Time Factors
Transfection
Abstract
Acidic pH of the Golgi lumen is known to be crucial for correct glycosylation, transport and sorting of proteins and lipids during their transit through the organelle. To better understand why Golgi acidity is important for these processes, we have examined here the most pH sensitive events in N-glycosylation by sequentially raising Golgi luminal pH with chloroquine (CQ), a weak base. We show that only a 0.2 pH unit increase (20 microM CQ) is sufficient to markedly impair terminal alpha(2,3)-sialylation of an N-glycosylated reporter protein (CEA), and to induce selective mislocalization of the corresponding alpha(2,3)-sialyltransferase (ST3) into the endosomal compartments. Much higher pH increase was required to impair alpha(2,6)-sialylation, or the proximal glycosylation steps such as beta(1,4)-galactosylation or acquisition of Endo H resistance, and the steady-state localization of the key enzymes responsible for these modifications (ST6, GalT I, MANII). The overall Golgi morphology also remained unaltered, except when Golgi pH was raised close to neutral. By using transmembrane domain chimeras between the ST6 and ST3, we also show that the luminal domain of the ST6 is mainly responsible for its less pH sensitive localization in the Golgi. Collectively, these results emphasize that moderate Golgi pH alterations such as those detected in cancer cells can impair N-glycosylation by inducing selective mislocalization of only certain Golgi glycosyltransferases.
PubMed ID
19277980 View in PubMed
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Enhanced Abeta40 deposition was associated with increased Abeta42-43 in cerebral vasculature with Dutch-type hereditary cerebral hemorrhage with amyloidosis (HCHWA-D).

https://arctichealth.org/en/permalink/ahliterature187365
Source
Ann N Y Acad Sci. 2002 Nov;977:149-54
Publication Type
Article
Date
Nov-2002
Author
K. Ozawa
T. Tomiyama
M L Maat-Schieman
R A Roos
H. Mori
Author Affiliation
Department of Neuroscience, Institute of Gerontology, Osaka City University, 1-4-3 Asahimachi, Abenoku, Osaka 545-8585, Japan.
Source
Ann N Y Acad Sci. 2002 Nov;977:149-54
Date
Nov-2002
Language
English
Publication Type
Article
Keywords
Amyloid beta-Peptides - genetics
Amyloidosis, Familial - genetics - pathology
Animals
COS Cells
Cercopithecus aethiops
Cerebral Hemorrhage - genetics - pathology
Cerebrovascular Circulation - physiology
Humans
Mice
Mutation
Netherlands
Peptide Fragments - genetics
Sweden
Transfection
Abstract
Cerebrovascular deposition of the amyloid beta-protein (Abeta) is a common pathologic event in patients with Alzheimer's disease (AD) and certain related disorders. Such an Abeta vascular deposition occurs primarily in the medial layer of the cerebral vessel wall in an assembled fibrillar state. These deposits are associated with several pathological responses, including degeneration of the smooth muscle cells in the cerebral vessel wall. Severe cases of cerebrovascular Abeta deposition are also accompanied by loss of vessel wall integrity and hemorrhagic stroke. Although the reasons for this pathological consequence are unclear, altered proteolytic mechanisms within the cerebral vessel wall may be involved. We analyzed cerebral Abeta deposition in brains with AD and Dutch-type hereditary cerebral hemorrhage with amyloidosis (HCHWA-D) on the basis of two amyloid species of Abeta(40) and Abeta(42/43) using specific monoclonal antibodies. Compared to Abeta deposition in senile plaques, the molecular composition of Abeta was distinguishable, indicating that the Abeta(40) species is the main component for vascular amyloid. Furthermore, we found Abeta(42/43) immunoreactivity was also much increased in amyloid angiopathy of all cases with HCHWA-D. Taken together, amyloid angiopathy in HCHWA-D may share an Abeta(42)-driven deposition mechanism with plaque amyloid, resulting in enhanced Abeta(40) deposition.
PubMed ID
12480745 View in PubMed
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Familial lipoprotein lipase (LPL) deficiency: a catalogue of LPL gene mutations identified in 20 patients from the UK, Sweden, and Italy.

https://arctichealth.org/en/permalink/ahliterature34443
Source
Hum Mutat. 1997;10(6):465-73
Publication Type
Article
Date
1997
Author
F. Mailly
J. Palmen
D P Muller
T. Gibbs
J. Lloyd
J. Brunzell
P. Durrington
K. Mitropoulos
J. Betteridge
G. Watts
H. Lithell
F. Angelico
S E Humphries
P J Talmud
Author Affiliation
Department of Medicine, University College London Medical School, UK.
Source
Hum Mutat. 1997;10(6):465-73
Date
1997
Language
English
Publication Type
Article
Keywords
Adult
Animals
COS Cells
Child
Child, Preschool
DNA Mutational Analysis
Genes - genetics
Genetic Heterogeneity
Genotype
Great Britain
Heterozygote Detection
Humans
Infant
Infant, Newborn
Italy
Lipoprotein Lipase - deficiency - genetics - metabolism
Lipoprotein Lipase Deficiency, Familial - blood - genetics
Middle Aged
Mutation - genetics
Phenotype
Polymorphism, Single-Stranded Conformational
Research Support, Non-U.S. Gov't
Sweden
Triglycerides - blood
Abstract
The aim of this study was to identify mutations in the lipoprotein lipase (LPL) gene in 20 unrelated patients with familial lipoprotein deficiency (FLLD) and to investigate the genotype/phenotype relationship. The previously reported G188E mutation (Monsalve et al., J Clin Invest 86:728-734, 1990) was screened for and found to be present in seven individuals (12/40 alleles). In addition, three patients were heterozygous for the 2.0 kb insertion (Langlois et al., Proc Nalt Acad Sci US 86:948-952, 1989). Two approaches were taken for new mutation detection; single-strand conformation polymorphism and sequencing to identify micro-mutations in the proximal promoter and exons 1-9 of the LPL gene and Southern blotting to identify gross mutations. Ten different point mutations were found (W86G, A158T, H183Q, G188E, S193R, P207L, L252X, N291S, M301T, L303P). Additionally, a two nucleotide deletion in exon 6 (delta1006-1007), a six nucleotide deletion in exon 8 (delta1441-1447), and a silent substitution in the wobble position of codon E118 were identified. In vitro mutagenesis and expression in COS-B cells suggested that the A158T and S193R substitutions virtually abolished enzyme activity. In analysing the genotype/phenotype relationship, there was no strong association between age at diagnosis, severity of symptoms, lipid levels, and the nature/position of the mutation. Triglyceride levels, however, were higher in compound heterozygotes compared to true homozygotes, possibly reflecting increased instability of heterodimers. Overall, 29 of 40 (72.5%) mutant alleles were identified. Failure to identify the mutation in 11 alleles might reflect the inadequacy of the method or the possibility that mutations lie within regions of the gene not screened in the study because of lack of availability of sequence.
PubMed ID
9401010 View in PubMed
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28 records – page 1 of 3.