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Titolo:
T-]G OR T-]A MUTATION INTRODUCED IN THE BRANCHPOINT CONSENSUS SEQUENCE OF INTRON-4 OF LECITHIN-CHOLESTEROL ACYLTRANSFERASE (LCAT) GENE - INTRON RETENTION CAUSING LCAT DEFICIENCY
Autore:
LI M; KUIVENHOVEN JA; AYYOBI AF; PRITCHARD PH;
Indirizzi:
ST PAULS HOSP,DEPT LAB MED & PATHOL,ARTHEROSCLEROSIS SPECIALTY LAB,1081 BURRARD ST VANCOUVER BC V6Z 1Y6 CANADA ST PAULS HOSP,DEPT LAB MED & PATHOL,ARTHEROSCLEROSIS SPECIALTY LAB VANCOUVER BC V6Z 1Y6 CANADA UNIV BRITISH COLUMBIA VANCOUVER BC V6Z 1Y6 CANADA
Titolo Testata:
Biochimica et biophysica acta, L. Lipids and lipid metabolism
fascicolo: 2, volume: 1391, anno: 1998,
pagine: 256 - 264
SICI:
0005-2760(1998)1391:2<256:TOTMII>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
FISH-EYE DISEASE; RNA SPLICING INVITRO; AMINO-ACID EXCHANGE; MESSENGER-RNA; MOLECULAR DEFECT; SITE; EXPRESSION; SPLICEOSOME; SELECTION;
Keywords:
LECITHIN-CHOLESTEROL ACYLTRANSFERASE DEFICIENCY; SITE-DIRECTED MUTAGENESIS; INTRON MUTATION; BRANCHPOINT SEQUENCE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
35
Recensione:
Indirizzi per estratti:
Citazione:
M. Li et al., "T-]G OR T-]A MUTATION INTRODUCED IN THE BRANCHPOINT CONSENSUS SEQUENCE OF INTRON-4 OF LECITHIN-CHOLESTEROL ACYLTRANSFERASE (LCAT) GENE - INTRON RETENTION CAUSING LCAT DEFICIENCY", Biochimica et biophysica acta, L. Lipids and lipid metabolism, 1391(2), 1998, pp. 256-264

Abstract

Previous mutations associated with lecitin:cholesteryl acyltransferase (LCAT) deficiency syndromes have been identified in the coding regions of the LCAT gene. However, recently, an intron mutation was found in a family in which three sisters presented with fish-eye disease (FED). The probands were shown to be heterozygotes for a mutation in intron 4. The respective T --> C nucleotide substitution, 22 basis upstreamof the 3'-splice site, causes a null allele as the result of completeintron retention. Since the natural mutation occurs in a putative branchpoint consensus sequence of the intron, it was hypothesized that the point mutation may disrupt the splicing of the pre-mRNA. To further study the functional significance of the above thymine residue in the branchpoint sequence, we introduced other nucleotides at this position, i.e., LCAT Int-4 MUT-1 (T --> G) and LCAT Int-4 MUT-2 (T --> A). After stable transfection of the mutated pNUT-LCAT minigenes into BHK cells, we could detect neither LCAT activity nor LCAT protein in the culture medium of the pNUT-LCAT Int-4 MUT-1 and pNUT-LCAT Int-4 MUT-2 celllines, as was previously described for the natural mutation. To determine the effects of the introduced mutations on pre-mRNA splicing, total RNA from transfected BHK cells was used for RT-PCR analysis. All BHK cell lines went shown to transcribe the integrated LCAT minigenes. However, the sizes of these LCAT messengers indicated that intron 4 wasretained in the pNUT-LCAT Int-4 MUT-1 and pNUT-LCAT Int-4 MUT-2 cell lines. Subsequent sequence analysis of the RT-PCR products demonstrated that the unspliced intronic sequences contained the introduced mutations. in conclusion, the observed retention of intron 4 of the LCAT gene is the result of the specific loss of a thymine residue two bases upstream of the branchpoint adenosine residue in the putative branchpoint consensus sequence. The results confirm that a single base change in the branchpoint consensus sequence of an intron can cause human disease although this sequence is poorly conserved in mammals. (C) 1998 Elsevier Science B.V.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/11/20 alle ore 18:58:59