Two mutations in the same low-density lipoprotein receptor allele act in synergy to reduce receptor function in heterozygous familial hypercholesterolemia

Jensen, Henrik Kjærulf; Jensen, Thomas G.; Færgeman, Ole; Jensen, L.G.; Andresen, Brage S.; Corydon, Morten J.; Andreasen, Per Hove; Hansen, Peter S.; Heath, Finn; Bolund, Lars; Gregersen, Niels

doi:10.1002/(sici)1098-1004(1997)9:5<437::aid-humu10>3.0.co;2-3

Cited by 26 publications

(13 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…segregation studies. Both the T705I/1061‐10C>T (13) and the N543/FsL777 (22) mutations have previously been shown to be in linkage disequilibrium. Our results confirmed this observation in one family for the former and in two families for the latter combination.…”

Section: Discussionmentioning

confidence: 99%

Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia

et al. 2006

View full text Add to dashboard Cite

The lipid disorder familial hypercholesterolemia (FH) predisposes to cardiovascular disease. With a prevalence of approximately one in 500 in the general Caucasian population, FH is one of the most frequent single-gene disorders. As the mutational spectra vary between populations, it is crucial to identify the mutations in a given population in order to implement a molecular genetic screening strategy. A total of 1053 referred individuals with clinical signs of FH were investigated, and mutations were identified in 425 individuals. Fifty-four different mutations were identified, of which 13 are novel. The five most frequent mutations accounted for 56.3% of all disease-causing mutations. The majority of the remaining mutations were of a private nature only encountered in single families. In this study, a reliable molecular genetic screening protocol was established, and the relevance of performing presymptomatic genetic analysis as part of a preventive strategy was documented. We have acquired knowledge of the mutational spectra in the Danish population and thus will be able to trace mutations in their relatives through our index cases.

show abstract

Section: Discussionmentioning

confidence: 99%

Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia

et al. 2006

View full text Add to dashboard Cite

show abstract

“…For FH this is known to occur, for example the LDLreceptor was found to be defective when the N543H and 2393del9 mutations occurred together on the same allele, while receptor function was not greatly impaired when only one of the mutations was present. 52 If cascade screening were to be implemented then such double mutations on the same alleles might be missed, and thus additional care must be taken in predicting if a detected mutation is pathogenic (Figure 2).…”

Section: Screening Strategiesmentioning

confidence: 99%

A molecular genetic service for diagnosing individuals with familial hypercholesterolaemia (FH) in the United Kingdom

et al. 2001

View full text Add to dashboard Cite

A genetic diagnostic service for familial hypercholesterolaemia (FH) has been established over the last 4 years in the Clinical Molecular Genetics Laboratory at Great Ormond Street Hospital for Children NHS Trust (GOSH), London. In total there have been 368 referrals; 227 probands and 141 family members, which have come from a number of lipid clinics and from general practitioners. FH is caused by mutations in the lowdensity lipoprotein receptor gene (LDLR) and these are analysed by SSCP, DNA sequencing and direct assays. The clinically indistinguishable disorder, familial defective apolipoprotein B100 (FDB) is caused by one of three mutations in the apolipoprotein B100 gene (APOB) which are analysed by direct assays. Mutations predicted to be pathogenic were found in 76 probands, 67 in LDLR (23 previously undescribed) and nine in APOB. The mutation detection rate was 53% in paediatric probands, 32% in adults with a`definite' FH diagnosis (tendon xanthoma positive) and 14% in adults with a`possible' FH diagnosis (tendon xanthoma negative). The predicted loss of sensitivity that would result from reducing the number of exons tested has been assessed, and a molecular screening strategy suitable for UK patients is proposed. A similar strategy may be useful for other countries where genetic heterogeneity results in a wide mutation spectrum for FH.

show abstract

“…In particular, carriers of the N543H/2393del9 mutation had less abnormal lipid profiles and accordingly lower CVD risk, compared with carriers of other mutations. The allelic combination of the N543H and 2393del9 mutations has been described as a functional class 2 defect (transport deficient), 17 but its mild phenotype was first noticed in this study.…”

Section: Discussionmentioning

confidence: 60%

Low-Density Lipoprotein Receptor Gene Mutations and Cardiovascular Risk in a Large Genetic Cascade Screening Population

et al. 2002

View full text Add to dashboard Cite

Background-A large cohort of patients with familial hypercholesterolemia (FH), free from selection for cardiovascular disease (CVD), and their unaffected relatives was collected by genetic cascade screening and examined for the influence of different mutations of the LDL receptor gene on lipoprotein levels and the risk of CVD. Multivariate analyses with adjustment for age, sex, and specific family ties were performed. Methods and Results-Significant variation of LDL levels was observed among 399 patients with FH with different mutations. Null alleles were associated with more severely elevated LDL cholesterol, whereas the frequent N543H/2393del9 mutation led to less elevated LDL cholesterol.

show abstract

Two mutations in the same low-density lipoprotein receptor allele act in synergy to reduce receptor function in heterozygous familial hypercholesterolemia

Cited by 26 publications

References 23 publications

Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia

Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia

A molecular genetic service for diagnosing individuals with familial hypercholesterolaemia (FH) in the United Kingdom

Low-Density Lipoprotein Receptor Gene Mutations and Cardiovascular Risk in a Large Genetic Cascade Screening Population

Contact Info

Product

Resources

About