title: A 'de novo' point mutation of the low-density lipoprotein receptor gene in an Italian subject with primary hypercholesterolemia.
abstract: Severe hypercholesterolemia was found in an 11-year-old boy with no family history of familial hypercholesterolemia. The reduced LDL-receptor activity in cultured skin fibroblasts (40% 125I-LDL degradation as compared with a control cell line) indicated the presence of an LDL-receptor defect. The analysis of the promoter region and the exons of LDL-receptor gene by single strand conformation polymorphism revealed an abnormal migration pattern in exon 1, which was due to a T --> A transversion at nucleotide 28 of the cDNA. This novel mutation causes an arginine for tryptophane substitution at position - 12 of the signal peptide (W-12R) and introduces an AviII restriction site in exon 1. Screening of the mutation by polymerase chain reaction (PCR) amplification of exon 1 and AviII digestion revealed that none of the proband's family members carried the mutation. Non-paternity was excluded after the analysis of a battery of 14 short tandem repeats located in 13 different chromosomes. These results are consistent with the hypothesis that the proband is heterozygous for a 'de novo' mutation of the LDL-receptor gene producing a non-conservative amino acid substitution. We suggest that the change in the net charge of the signal peptide, caused by the addition of a positively charged amino acid, impairs the co-translational translocation of the nascent receptor protein across the endoplasmic reticulum membrane.
authors.affiliation: Department of Biomedical Science, Section of General Pathology, University of Modena, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Cassanelli
authors.forename: S
authors.initials: S
authors.lastname: Bertolini
authors.forename: M
authors.initials: M
authors.lastname: Rolleri
authors.forename: F
authors.initials: F
authors.lastname: De Stefano
authors.forename: L
authors.initials: L
authors.lastname: Casarino
authors.forename: N
authors.initials: N
authors.lastname: Elicio
authors.forename: A
authors.initials: A
authors.lastname: Naselli
authors.forename: S
authors.initials: S
authors.lastname: Calandra
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D002784:Cholesterol / Q000097:blood; D005091:Exons / Q000235:genetics; D005192:Family Health; D005220:Fathers; D005796:Genes / Q000235:genetics*; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009035:Mothers; D009679:Nuclear Family; D017354:Point Mutation / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics*
chemical_list: D011973:Receptors, LDL; D002784:Cholesterol