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.
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Daga A, Mattioni T, Balestreri R, Coviello DA, Bertolini S (1990) Use of three DNA polymorphisms of the LDL receptor gene in the diagnosis of familial hypercholesterolemia. Hum Genet 84:412–416
Daniel TO, Schneider WJ, Goldstein JL, Brown MS (1983) Visualization of lipoprotein receptors by ligand blotting. J Biol Chem 258:4606–4611
Esser V, Limbird LE, Brown MS, Goldstein JL, Russell DW (1988) Mutational analysis of the ligand binding domain of the low density lipoprotein receptor. J Biol Chem 263:13282–13290
Goldstein JL, Brown MS (1989) Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease, 6th edn. McGraw-Hill, New York, pp 1214–1250
Hobbs HH, Russell DW, Brown MW, Goldstein JL (1990) The LDL-receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Annu Rev Genet 24:133–170
Hobbs HH, Brown MS, Goldstein JL (1992) Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat 1:445–466
Kowal RC, Herz J, Weisgraber KH, Mahley RW, Brown MS, Goldstein JL (1990) Opposing effects of apolipoproteins E and C on lipoprotein binding to low density lipoprotein receptorrelated protein. J Biol Chem 265:10771–10779
Leitersdorf E, Tobin EJ, Davignon J, Hobbs HH (1990) Common low density lipoportein receptor mutations in the French Canadian population. J Clin Invest 85:1014–1023
Lelli N, Ghisellini M, Gualdi R, Tiozzo R, Calandra S, Gaddi A, Ciarrocchi A, Arca M, Fazio S, Coviello DA, Bertolini S (1991) Characterization of three mutations of LDL receptor gene in Italian patients with familial hypercholesterolemia. Arterioscler Thromb 11:234–243
Lelli N, Garuti R, Zambelli F, Cassanelli S, Tiozzo R, Corsini A, Bertolini S, Ortisi MT, Bellu' R, Calandra S (1993) Alternative splicing of mutant LDL-receptor mRNA in an Italian patient with familial hypercholesterolemia due to a partial deletion of DL-receptor gene (FHPOTENZA). J Lipid Res 34:1347–1354
Metha KD, Chen WJ, Goldstein JL, Brown MS (1991) The low density lipoprotein receptor in Xenopus laevis. I. Five domains that resemble the human receptor. J Biol Chem 266:10406–10414
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Lelli, N., Garuti, R., Pedrazzi, P. et al. A new missense mutation (Cys297→Phe) of the low density lipoprotein receptor in Italian patients with familial hypercholesterolemia (FHTrieste). Hum Genet 93, 538–540 (1994). https://doi.org/10.1007/BF00202819
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DOI: https://doi.org/10.1007/BF00202819