A double heterozygote for familial hypercholesterolaemia and familial defective apolipoprotein B-100

Taylor, Alison; Bayly, Graham; Patel, Kavisha; Yarram, L.; Williams, Maggie; Shield, Julian P H; Humphries, Steve E.; Norbury, Gail

doi:10.1258/acb.2010.010089

Cited by 17 publications

(7 citation statements)

References 18 publications

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“…These findings demonstrate that exome sequencing can help in the diagnosis and the identification of compound heterozygotes in ADH. In fact, some studies described patients and families with both LDLR/APOB 31 – 36 , or LDLR/PCSK9 mutations 37 , 38 . However, the clinical characteristics of double-heterozygous ADH patients are underreported and the diagnosis of double-heterozygous ADH can be easily missed 39 .…”

Section: Discussionmentioning

confidence: 99%

New Sequencing technologies help revealing unexpected mutations in Autosomal Dominant Hypercholesterolemia

Elbitar

Susan‐Resiga

Ghaleb

et al. 2018

Sci Rep

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Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated LDL-C levels leading to coronary heart disease. Four genes are implicated in ADH: LDLR, APOB, PCSK9 and APOE. Our aim was to identify new mutations in known genes, or in new genes implicated in ADH. Thirteen French families with ADH were recruited and studied by exome sequencing after exclusion, in their probands, of mutations in the LDLR, PCSK9 and APOE genes and fragments of exons 26 and 29 of APOB gene. We identified in one family a p.Arg50Gln mutation in the APOB gene, which occurs in a region not usually associated with ADH. Segregation and in-silico analysis suggested that this mutation is disease causing in the family. We identified in another family with the p.Ala3396Thr mutation of APOB, one patient with a severe phenotype carrying also a mutation in PCSK9: p.Arg96Cys. This is the first compound heterozygote reported with a mutation in APOB and PCSK9. Functional studies proved that the p.Arg96Cys mutation leads to increased LDL receptor degradation. This work shows that Next-Generation Sequencing (exome, genome or targeted sequencing) are powerful tools to find new mutations and identify compound heterozygotes, which will lead to better diagnosis and treatment of ADH.

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Section: Discussionmentioning

confidence: 99%

New Sequencing technologies help revealing unexpected mutations in Autosomal Dominant Hypercholesterolemia

Elbitar

Susan‐Resiga

Ghaleb

et al. 2018

Sci Rep

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“…It is also now known that 2-10% of patients with a clinical diagnosis of FH have the apoB R3500Q mutation ( 289,297,298 ), including some who also have a LDLR mutation (299)(300)(301). Compound heterozygote ADH-1/2 patients tend to have higher LDL-C, more extensive xanthomatosis, and more severe premature CHD than heterozygote ADH-1 and homozygote ADH-2 patients ( Table 6 ).…”

Section: Apob Mutations Defective Ldlr Binding and Adh-2mentioning

confidence: 99%

Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk

Calandra

Tarugi

Speedy

et al. 2011

Journal of Lipid Research

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This review covers the dietary and biochemical origins and fates of key classes of sterol molecules in humans, namely, cholesterol and the relatively under-recognized and often unappreciated noncholesterol sterols and stanols; the intra-and intercellular systems that govern their transport; and the contribution of innate genetic programs to the biochemically observed levels of plasma LDL-cholesterol (LDL-C). The reasons for these foci are both biological and medical. The former is the burgeoning knowledge of the normal physiological roles that cholesterol performs within cell membranes in supporting receptor-mediated signaling activities ( 1-4 ), the movement of diverse molecules through different membranebound compartments (5)(6)(7)(8), and multiple other cell functions (9)(10)(11), including myelination ( 12 ). The latter, Abstract This review integrates historical biochemical and modern genetic fi ndings that underpin our understanding of the low-density lipoprotein (LDL) dyslipidemias that bear on human disease. These range from life-threatening conditions of infancy through severe coronary heart disease of young adulthood, to indolent disorders of middle-and oldage. We particularly focus on the biological aspects of those gene mutations and variants that impact on sterol absorption and hepatobiliary excretion via specifi c membrane transporter systems ( NPC1L1 , ABCG5/8 ); the incorporation of dietary sterols ( MTP ) and of de novo synthesized lipids ( HMGCR, TRIB1 ) into apoB-containing lipoproteins ( APOB ) and their release into the circulation ( ANGPTL3, SARA2, SORT1 ); and receptor-mediated uptake of LDL and of intestinal and hepatic-derived lipoprotein remnants ( LDLR, APOB, APOE, LDLRAP1, PCSK9, IDOL ).The insights gained from integrating the wealth of genetic data with biological processes have important implications for the classifi cation of clinical and presymptomatic diagnoses of traditional LDL dyslipidemias, sitosterolemia, and newly emerging phenotypes, as well as their management through both nutritional and pharmaceutical means. -Calandra, S., P. Tarugi Abbreviations: ABCG5, ATP-binding cassette, subfamily G, member 5; ABCG8, ATP-binding cassette, subfamily G, member 8; ABL, abetalipoproteinemia; ADH, autosomal dominant hypercholesterolemia; ANGPTL3, angiopoietin-like 3; ARH, autosomal recessive hypercholesterolemia; BMI, body mass index; CAC, coronary artery calcifi cation; CAD, coronary artery disease; CHD, coronary heart disease; CMRD, chylomicron retention disease; CYP7A1 , cholesterol 7 ␣ -hydroxylase; EGF, epidermal growth factor; ER, endoplasmic reticulum; FCHL, familial combined hyperlipidemia; FDB, familial defective apoB; FH, familial hypercholesterolemia; FHBL, familial hypobetalipoproteinemia; GWAS, genome-wide association study; HMGCR, HMGCoA reductase; IDOL, inducible degrader of LDLR; LD, linkage disequilibrium; LDL-C, LDL-cholesterol; LDLR, LDL receptor; LRP1, LDLRAP1, LDLR-associated protein 1; LDLR-related protein 1; LXR, liver X receptor; MI, myocardial infarction; MTP, m...

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“…Moreover, p.R3531C mutation has been associated with plasma cholesterol levels varying over a wide range and has also been reported a normocholesterolaemic phenotype 22 . Subjects with both FH and FDB are rare and there have been only three reports in the literature of such compounds heterozygotes 23–25 …”

Section: Figurementioning

confidence: 99%

Lack of phenotypic additive effect of familial defective apolipoprotein B3531 in familial hypercholesterolaemia

Giammanco

Spina

Fayer

et al. 2021

Internal Medicine Journal

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Familial defective apolipoprotein (apo) B (FDB) and familial hypercholesterolaemia (FH) are the two common genetic conditions that cause hypercholesterolaemia. R3531C mutation of the APOB gene is a rare cause of FDB. Individuals with both FDB and FH are rare. A 51‐year‐old man with hypercholesterolaemia (11.4 mmol/L) and his family were studied. Low‐density lipoprotein (LDL) receptor (LDLR) and APOB genes were analysed by direct sequencing. LDL of four subjects were studied in a fibroblast LDL receptor‐binding displacement assay. We found a mutation of the LDLR gene (p.Y398X) in the proband and in four other family members: the p.R3531C APOB gene mutation was also found in the proband, his father and his children. The proband and his son were thus compound heterozygotes for both FH and FDB. Double heterozygotes did not show higher cholesterol levels compared to carriers of LDLR gene mutation alone. LDL from one of the carriers of the p.R3531C alone exhibited a binding ability, which was similar to a normal subject. This is the first report in Italy of the p.R3531C mutation, and our results show that this mutation has no effect in LDLR p.Y398X/APOB p.R3531C double heterozygotes.

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A double heterozygote for familial hypercholesterolaemia and familial defective apolipoprotein B-100

Cited by 17 publications

References 18 publications

New Sequencing technologies help revealing unexpected mutations in Autosomal Dominant Hypercholesterolemia

New Sequencing technologies help revealing unexpected mutations in Autosomal Dominant Hypercholesterolemia

Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk

Lack of phenotypic additive effect of familial defective apolipoprotein B3531 in familial hypercholesterolaemia

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