Missense Mutation in the LDLR Gene: A Wide Spectrum in the Severity of Familial Hypercholesterolemia

Varret, Mathilde; Rabès, Jean-Pierre

doi:10.5772/36432

Cited by 12 publications

(26 citation statements)

References 61 publications

(39 reference statements)

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“…Here, we report the expansion of the zebrafi sh hypercholesterolemia model to include hypercholesterolemia as a result of genetic manipulation. The LDLR plays a well-understood role in LDL endocytosis, and mutations in the LDLRencoding gene ( LDLR ) are associated with elevated plasma LDL-c levels and familial hypercholesterolemia (36)(37)(38)(39)(40). Our results demonstrate the feasibility of the zebrafi sh model through transient knockdown of the zebrafi sh homolog of LDLR, ldlr , by morpholino (MO), which resulted in hypercholesterolemia.…”

Section: Quantitative Rt-pcrmentioning

confidence: 70%

“…Our MO resulted in removal of part of the R5 ligand binding domain which is essential for both apoB-100-mediated LDL binding and apoE-mediated lipoprotein binding ( 46,48,49,83 ). Interestingly, over 50 mutations have been identifi ed in familial hypercholesterolemia within this region of the human LDLR gene ( 40,(84)(85)(86)(87).…”

Section: Increased Liver Lipid Accumulation and Hepatomegaly In Ldlr mentioning

confidence: 99%

“…Though we did not investigate the extent to which Ldlr-apolipoprotein interaction was disrupted in our morphants, sequence confi rmation of the partial removal of a ligand binding region of the receptor suggests a likely mechanism by which the MO disrupts Ldlr function. The exon targeted for deletion, exon 4, encompasses the ligand binding regions LR3-5, which are essential for mediating the interaction with lipoproteins ( 40,49 ). Our MO resulted in removal of part of the R5 ligand binding domain which is essential for both apoB-100-mediated LDL binding and apoE-mediated lipoprotein binding ( 46,48,49,83 ).…”

Section: Increased Liver Lipid Accumulation and Hepatomegaly In Ldlr mentioning

confidence: 99%

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Disruption of ldlr causes increased LDL-c and vascular lipid accumulation in a zebrafish model of hypercholesterolemia

O’Hare

Wang

Montasser

et al. 2014

Journal of Lipid Research

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Hypercholesterolemia is a primary cause of atherosclerosis and subsequent cardiovascular events. Genetic factors play a major role in regulation of plasma cholesterol levels, with heritability estimated to range from 40 to 70% [reviewed in ( 1 )]. Over 100 genomic regions have been associated with changes in plasma lipid levels ( 2-5 ). Despite the large number of putative candidate genes identifi ed, the functions of many remain largely unknown, owing in part to the lack of physiologically relevant in vivo models with which to validate and characterize the functionality of associated variants ( 3, 4, 6-13 ). Development of novel models in which genes can be individually targeted will likely reveal functional roles for genetic determinants of blood lipid levels and may facilitate discovery of novel targets for drug development.The zebrafi sh is an excellent candidate for establishing genetic models of hyperlipidemia due to conservation of cell types and molecular pathways involved in lipid metabolism and cholesterol synthesis ( 8,(14)(15)(16)(17)(18)(19)(20). These include hepatocytes, adipocytes, and pancreatic acinar cells ( 17 ) as well as expression of genes involved in lipid transport and metabolism, such as LDL receptor ( ldlr ), sterol regulatory element binding protein ( srebp ) 1/2 , and HMG-CoA reductase ( Hmgcr ) ( 18-29 ). Consequently, mechanisms of lipid metabolism, storage, absorption, and transport are highly conserved in zebrafi sh, allowing for physiologically relevant investigation of these processes ( 20,28,(30)(31)(32)(33)(34). Moreover, targeted suppression of gene expression can be easily achieved in zebrafi sh embryos, making assessment of the resulting larval phenotypes feasible for a large number

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Section: Quantitative Rt-pcrmentioning

confidence: 70%

Section: Increased Liver Lipid Accumulation and Hepatomegaly In Ldlr mentioning

confidence: 99%

Section: Increased Liver Lipid Accumulation and Hepatomegaly In Ldlr mentioning

confidence: 99%

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Disruption of ldlr causes increased LDL-c and vascular lipid accumulation in a zebrafish model of hypercholesterolemia

O’Hare

Wang

Montasser

et al. 2014

Journal of Lipid Research

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“…Risks for the development of cardiovascular disease (CVD) include lifestyle choices and environmental factors, but a subgroup of the population develop early CVD primarily due to inheritable genetic mutations in the low‐density lipoprotein receptor (LDLR). Familial hypercholesterolemia (FH) is an autosomal dominant disease causing extremely elevated low‐density lipoprotein‐cholesterol (LDL‐C) and premature CVD . Over 1,200 LDLR mutations have been identified that lead to a wide spectrum of disease severity depending on the mutation's effect on LDLR activity .…”

Section: Introductionmentioning

confidence: 99%

CRISPR correction of a homozygous low‐density lipoprotein receptor mutation in familial hypercholesterolemia induced pluripotent stem cells

Omer

Hudson

Zheng

et al. 2017

Hepatology Communications

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Familial hypercholesterolemia (FH) is a hereditary disease primarily due to mutations in the low‐density lipoprotein receptor (LDLR) that lead to elevated cholesterol and premature development of cardiovascular disease. Homozygous FH patients (HoFH) with two dysfunctional LDLR alleles are not as successfully treated with standard hypercholesterol therapies, and more aggressive therapeutic approaches to control cholesterol levels must be considered. Liver transplant can resolve HoFH, and hepatocyte transplantation has shown promising results in animals and humans. However, demand for donated livers and high‐quality hepatocytes overwhelm the supply. Human pluripotent stem cells can differentiate to hepatocyte‐like cells (HLCs) with the potential for experimental and clinical use. To be of future clinical use as autologous cells, LDLR genetic mutations in derived FH‐HLCs need to be corrected. Genome editing technology clustered‐regularly‐interspaced‐short‐palindromic‐repeats/CRISPR‐associated 9 (CRISPR/Cas9) can repair pathologic genetic mutations in human induced pluripotent stem cells. Conclusion: We used CRISPR/Cas9 genome editing to permanently correct a 3‐base pair homozygous deletion in LDLR exon 4 of patient‐derived HoFH induced pluripotent stem cells. The genetic correction restored LDLR‐mediated endocytosis in FH‐HLCs and demonstrates the proof‐of‐principle that CRISPR‐mediated genetic modification can be successfully used to normalize HoFH cholesterol metabolism deficiency at the cellular level. (Hepatology Communications 2017;1:886–898)

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“…We targeted nucleotide substitutions due to transitions that involve interchanges of either two-ring purines (G>A) or onering pyrimidines (C>T) as well as transversions that interchange purine for pyrimidine bases (G>C) and involve exchange of one-ring and two-ring structures. The LDLR c.487dupC frameshift mutation identified in our local population involves insertion of a cytosine (C) in a run of 5 consecutive C, a pattern seen in half of the insertion cases in LDLDR, where the single nucleotide insertion occurs within runs of 2-7 identical bases (27). All methods demonstrated excellent analytical performance, even when the DNA template used had less than optimal quality and quantity.…”

Section: Discussionmentioning

confidence: 99%

Cascade Screening for Familial Hypercholesterolemia: PCR Methods with Melting-Curve Genotyping for the Targeted Molecular Detection of Apolipoprotein B and LDL Receptor Gene Mutations to Identify Affected Relatives

Pandey

Leider

Khan

et al. 2016

The Journal of Applied Laboratory Medicine

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Background: A key objective of the UK National Institute for Health and Care Excellence (NICE) pathway for diagnosis of familial hypercholesterolemia (FH) is the identification of affected relatives of index cases through cascade screening. At present, there is no systematic appraisal of available methodological options to identify the appropriate diagnostic testing protocol that would allow cost-effective cascade genetic screening. The majority of FH-causing mutations identified in the LDL receptor (LDLR) or apolipoprotein B (APOB) genes are single-nucleotide changes. This pattern of mutations suggests that PCR methods using melting curve-based genotyping might offer a convenient methodological approach for screening relatives. Methods: We developed and validated one-tube PCR methods for the mutations APOB c.10580G>A (p.Arg3527Gln), LDLR c.1474G>A (p.Asp492Asn), and c.2054C>T (p.Pro685Leu) and 3 novel LDLR mutations identified in the Coventry and Warwickshire population: LDLR c.1567G>C (p.Val523Leu), c.487dupC (p.Gln163Profs17), and c.647G>C (p.Cys216Ser). Results: These methods successfully amplified target sequence from genomic DNA extracted from either peripheral blood or saliva. They also demonstrated acceptable analytical performance characteristics (specificity of amplification, repeatability, and reproducibility) over a wide range of DNA concentrations and purity. This approach was used for cascade testing of relatives of index FH cases with confirmed mutations and identified family members with high plasma LDL cholesterol as heterozygous for disruptive alleles. Conclusions: Our study generates proof-of-concept evidence of methods suitable for detecting single nucleotide substitutions and insertions that can deliver reliable, easy, low-cost, and rapid family screening of FH patients and can be adopted by nonspecialist molecular diagnostic laboratories.

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Missense Mutation in the LDLR Gene: A Wide Spectrum in the Severity of Familial Hypercholesterolemia

Cited by 12 publications

References 61 publications

Disruption of ldlr causes increased LDL-c and vascular lipid accumulation in a zebrafish model of hypercholesterolemia

Disruption of ldlr causes increased LDL-c and vascular lipid accumulation in a zebrafish model of hypercholesterolemia

CRISPR correction of a homozygous low‐density lipoprotein receptor mutation in familial hypercholesterolemia induced pluripotent stem cells

Cascade Screening for Familial Hypercholesterolemia: PCR Methods with Melting-Curve Genotyping for the Targeted Molecular Detection of Apolipoprotein B and LDL Receptor Gene Mutations to Identify Affected Relatives

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