A 'de novo' point mutation of the low-density lipoprotein receptor gene in an Italian subject with primary hypercholesterolemia

• Published in: Clinical genetics 1998-05, Vol.53 (5), p.391-395
• Main Authors: Cassanelli, S., Bertolini, S., Rolleri, M., Stefano, F De, Casarino, L., Elicio, N., Naselli, A., Calandra, S.
• Format: Article
• Language: English
• Subjects: 'de novo' mutation; Adolescent; Adult; Amino Acid Substitution; Biological and medical sciences; Cholesterol - blood; Disorders of blood lipids. Hyperlipoproteinemia; Exons - genetics; Family Health; Fathers; Genes - genetics; Humans; Hypercholesterolemia - blood; Hypercholesterolemia - epidemiology; Hypercholesterolemia - genetics; Italy - epidemiology; low-density lipoprotein receptor; Male; Medical sciences; Metabolic diseases; Middle Aged; Mothers; Nuclear Family; Point Mutation - genetics; primary hypercholesterolemia; Receptors, LDL - genetics; signal peptide
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/j.1399-0004.1998.tb02752.x

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.