Severe hypercholesterolemia was found in an Ii-year-old boy with no family history of familial hypercholesterolemia. The reduced LDL-receptor activity in cultured skill fibroblasts (40% I-125-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.

A 'de novo' point mutation of the low-density lipoprotein receptor gene in an Italian subject with primary hypercholesterolemia / Cassanelli, Stefano; S., Bertolini; M., Rolleri; F., De Stefano; L., Casarino; N., Elicio; A., Naselli; CALANDRA BUONAURA, Sebastiano. - In: CLINICAL GENETICS. - ISSN 0009-9163. - ELETTRONICO. - 53:(1998), pp. 391-395.

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

CASSANELLI, Stefano;CALANDRA BUONAURA, Sebastiano
1998

Abstract

Severe hypercholesterolemia was found in an Ii-year-old boy with no family history of familial hypercholesterolemia. The reduced LDL-receptor activity in cultured skill fibroblasts (40% I-125-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.
53
391
395
A 'de novo' point mutation of the low-density lipoprotein receptor gene in an Italian subject with primary hypercholesterolemia / Cassanelli, Stefano; S., Bertolini; M., Rolleri; F., De Stefano; L., Casarino; N., Elicio; A., Naselli; CALANDRA BUONAURA, Sebastiano. - In: CLINICAL GENETICS. - ISSN 0009-9163. - ELETTRONICO. - 53:(1998), pp. 391-395.
Cassanelli, Stefano; S., Bertolini; M., Rolleri; F., De Stefano; L., Casarino; N., Elicio; A., Naselli; CALANDRA BUONAURA, Sebastiano
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/307990
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