A new missense mutation (Cys297?Phe) of the low density lipoprotein receptor in Italian patients with familial hypercholesterolemia (FHTrieste)

During a survey of the mutations of the low density lipoprotein receptor (LDL-R) gene in Italian patients with familial hypercholesterolemia (FH), we identified a novel point mutation, that creates a new EcoRI site at the 5' end of exon 7, in a heterozygous FH subject (FH-100). The sequence of...

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Bibliographic Details
Published in:Human genetics 1994-05, Vol.93 (5), p.538-540, Article 538
Main Authors: LELLI, N, GARUTI, R, STEFANUTTI, C, CALANDRA, S, PEDRAZZI, P, GHISELLINI, M, SIMONE, M. L, TIOZZO, R, CATTIN, L, VALENTI, M, ROLLERI, M, BERTOLINI, S
Format: Article
Language:English
Subjects:
Base Sequence
Biological and medical sciences
Blotting, Southern
Cysteine
Disorders of blood lipids. Hyperlipoproteinemia
DNA - analysis
DNA Mutational Analysis
Exons - genetics
Female
Humans
Hyperlipoproteinemia Type II - genetics
Italy
Male
Medical sciences
Metabolic diseases
Molecular Sequence Data
Phenylalanine
Point Mutation
Polymerase Chain Reaction
Receptors, LDL - genetics
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Summary:During a survey of the mutations of the low density lipoprotein receptor (LDL-R) gene in Italian patients with familial hypercholesterolemia (FH), we identified a novel point mutation, that creates a new EcoRI site at the 5' end of exon 7, in a heterozygous FH subject (FH-100). The sequence of a cDNA fragment encompassing exon 7 showed the presence of a G-->T transversion in codon 297; this created a new EcoRI site and produced a missense mutation, leading to a Cys297-->Phe substitution in repeat A of the epidermal growth factor (EGF) precursor homology domain of LDL-R. Since the substitution of Cys297 disrupts the intracellular transport of the LDL-R protein, as previously demonstrated by site-directed mutagenesis, we suggest that this mutation is the cause of FH in the FH-100 proband. We screened the DNA of 303 Italian FH patients by amplification of exon 7 from genomic DNA followed by digestion with EcoRI or by Southern blotting. Two individuals (FH-64 and FH-127) were found to be carriers of the Cys297-->Phe mutation. Restriction fragment length polymorphism analysis demonstrated that, in two kindreds (FH-64 and FH-100), the haplotype in linkage with the Cys297-->Phe mutation was the same, suggesting the presence of a common ancestor. The Cys297-->Phe mutation has been designated FHTrieste after the name of the city in Northern Italy from which probands FH-100 and FH-127 originate.
ISSN:0340-6717
1432-1203
DOI:10.1007/BF00202819