title: A new missense mutation (Cys297-->Phe) of the low density lipoprotein receptor in Italian patients with familial hypercholesterolemia (FHTrieste).
abstract: 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.
authors.affiliation: Istituto di Patologia Generale, Università di Modena, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Lelli
authors.forename: R
authors.initials: R
authors.lastname: Garuti
authors.forename: P
authors.initials: P
authors.lastname: Pedrazzi
authors.forename: M
authors.initials: M
authors.lastname: Ghisellini
authors.forename: M L
authors.initials: ML
authors.lastname: Simone
authors.forename: R
authors.initials: R
authors.lastname: Tiozzo
authors.forename: L
authors.initials: L
authors.lastname: Cattin
authors.forename: M
authors.initials: M
authors.lastname: Valenti
authors.forename: M
authors.initials: M
authors.lastname: Rolleri
authors.forename: S
authors.initials: S
authors.lastname: Bertolini
mesh_terms: D001483:Base Sequence; D015139:Blotting, Southern; D003545:Cysteine; D004247:DNA / Q000032:analysis; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D007558:Italy; D008297:Male; D008969:Molecular Sequence Data; D010649:Phenylalanine; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011973:Receptors, LDL / Q000235:genetics*
chemical_list: D011973:Receptors, LDL; D010649:Phenylalanine; D004247:DNA; D003545:Cysteine