Normolipidemia and hypercholesterolemia in persons heterozygous for the same 1592+5G→A splice site mutation in the low-density lipoprotein receptor gene

A mutation display a clinical phenotype ranging from healthy normocholesterolemic persons to classical heterozygous familial hypercholesterolemia (FH) patients. Reverse transcription-polymerase chain reaction (RT-PCR) of RNA from Epstein Barr virus (EBV)-transformed lymphoblasts obtained from members of both families demonstrated abnormal splicing generating two aberrant mRNAs due to either alternative splicing and skipping of exon 10 or activation of a cryptic splice site in intron 10 inserting 66 intronic base pairs. These abnormally spliced mRNAs were predicted to encode two abnormal receptor proteins containing an in-frame deletion of 75 amino acids and an insertion of 22 novel amino acids, respectively. Results obtained by immunofluorescence staining, flow cytometry, and confocal microscopy of transfected Chang and COS-7 cells expressing normal and mutant LDL receptors were compatible with nearly complete retention of the mutant proteins in the endoplasmic reticulum. Quantitative measurements of LDL receptor mRNAs from EBV-transformed lymphoblasts, however, did not reveal any significant differences in variant mRNA contents between mutation carriers in the families that could be related to degree of hypercholesterolemia. -->
ISSN: 0009-9163
DOI: 10.1034/j.1399-0004.1999.560506.x
Přístupová URL adresa: https://explore.openaire.eu/search/publication?articleId=doi_________::e508b6a759ba49f36cc2b2644369ce8c
https://doi.org/10.1034/j.1399-0004.1999.560506.x
Rights: CLOSED
Přírůstkové číslo: edsair.doi...........e508b6a759ba49f36cc2b2644369ce8c
Autor: L. G. Jensen, Per Hove Andreasen, Henrik Jensen, Peter S. Hansen, Mogens Lytken Larsen, Henrik Uffe Holst, Ole Faergeman, Steen Kølvraa, Niels Gregersen, Lars Bolund
Rok vydání: 1999
Předmět:
Zdroj: Clinical Genetics. 56:379-389
ISSN: 0009-9163
DOI: 10.1034/j.1399-0004.1999.560506.x
Popis: In the present study, we have characterized a unique splice donor G to A substitution in the moderately conserved + 5 position in intron 10 of the low-density lipoprotein (LDL) receptor gene. In two Danish families, carriers of the 1592 + 5G --> A mutation display a clinical phenotype ranging from healthy normocholesterolemic persons to classical heterozygous familial hypercholesterolemia (FH) patients. Reverse transcription-polymerase chain reaction (RT-PCR) of RNA from Epstein Barr virus (EBV)-transformed lymphoblasts obtained from members of both families demonstrated abnormal splicing generating two aberrant mRNAs due to either alternative splicing and skipping of exon 10 or activation of a cryptic splice site in intron 10 inserting 66 intronic base pairs. These abnormally spliced mRNAs were predicted to encode two abnormal receptor proteins containing an in-frame deletion of 75 amino acids and an insertion of 22 novel amino acids, respectively. Results obtained by immunofluorescence staining, flow cytometry, and confocal microscopy of transfected Chang and COS-7 cells expressing normal and mutant LDL receptors were compatible with nearly complete retention of the mutant proteins in the endoplasmic reticulum. Quantitative measurements of LDL receptor mRNAs from EBV-transformed lymphoblasts, however, did not reveal any significant differences in variant mRNA contents between mutation carriers in the families that could be related to degree of hypercholesterolemia.
Databáze: OpenAIRE
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