Abstract:Familial hypercholesterolemia (FH) is one of the most common monogenic diseases, leading to an increased risk of premature atherosclerosis and its cardiovascular complications due to its effect on plasma cholesterol levels. Variants of three genes (
LDL-R
,
APOB
and
PCSK9
) are the major causes of FH, but in some probands, the FH phenotype is associated with variants of other genes. Alternatively, the typical clinical picture of FH can result… Show more
“…In approximately 90% of the cases, FH results from the presence of mutations in the LDLR gene itself ( 3 , 24 ). More than 1,700 different LDLR mutations have been described ( 25 , 26 ). LDLR mutations can either result in an absence of biosynthesis (class 1 defects), preclude the maturation/transportation of the receptor from the endoplasmic reticulum to the Golgi (class 2), reduce the affinity of the receptor for LDL particles (class 3), alter the internalization of the receptor/ligand complex (class 4), or prevent normal recycling of the LDLR back to the cell surface (class 5) ( 27 ) ( Fig.…”
Section: Genetics and Functional Characterization Of Fhmentioning
confidence: 99%
“…3 ). Only a handful of APOB mutations causing FH have been reported, and they are all located within (or in the vicinity of) the LDLR binding region of apoB100 ( 26 ). Fig.…”
Section: Genetics and Functional Characterization Of Fhmentioning
Familial hypercholesterolemia (FH) is one of the most common genetic disorders in humans. It is an extremely atherogenic metabolic disorder characterized by lifelong elevations of circulating LDL-C levels often leading to premature cardiovascular events. In this review, we discuss the clinical phenotypes of heterozygous and homozygous FH, the genetic variants in four genes (
LDLR/APOB/PCSK9/LDLRAP1
) underpinning the FH phenotype as well as the most recent in vitro experimental approaches used to investigate molecular defects affecting the LDL receptor pathway. In addition, we review perturbations in the metabolism of lipoproteins other than LDL in FH, with a major focus on lipoprotein (a). Finally, we discuss the mode of action and efficacy of many of the currently approved hypocholesterolemic agents used to treat patients with FH, with a special emphasis on the treatment of phenotypically more severe forms of FH.
“…In approximately 90% of the cases, FH results from the presence of mutations in the LDLR gene itself ( 3 , 24 ). More than 1,700 different LDLR mutations have been described ( 25 , 26 ). LDLR mutations can either result in an absence of biosynthesis (class 1 defects), preclude the maturation/transportation of the receptor from the endoplasmic reticulum to the Golgi (class 2), reduce the affinity of the receptor for LDL particles (class 3), alter the internalization of the receptor/ligand complex (class 4), or prevent normal recycling of the LDLR back to the cell surface (class 5) ( 27 ) ( Fig.…”
Section: Genetics and Functional Characterization Of Fhmentioning
confidence: 99%
“…3 ). Only a handful of APOB mutations causing FH have been reported, and they are all located within (or in the vicinity of) the LDLR binding region of apoB100 ( 26 ). Fig.…”
Section: Genetics and Functional Characterization Of Fhmentioning
Familial hypercholesterolemia (FH) is one of the most common genetic disorders in humans. It is an extremely atherogenic metabolic disorder characterized by lifelong elevations of circulating LDL-C levels often leading to premature cardiovascular events. In this review, we discuss the clinical phenotypes of heterozygous and homozygous FH, the genetic variants in four genes (
LDLR/APOB/PCSK9/LDLRAP1
) underpinning the FH phenotype as well as the most recent in vitro experimental approaches used to investigate molecular defects affecting the LDL receptor pathway. In addition, we review perturbations in the metabolism of lipoproteins other than LDL in FH, with a major focus on lipoprotein (a). Finally, we discuss the mode of action and efficacy of many of the currently approved hypocholesterolemic agents used to treat patients with FH, with a special emphasis on the treatment of phenotypically more severe forms of FH.
“…The most common monogenic disease leading to premature CVD is familial hypercholesterolemia (FH). FH has a frequency of approximately 1:200 and is caused primarily by mutations within the LDL receptor ( LDLR ), apolipoprotein B ( APOB ), and PCSK-9 genes [ 6 ]. The relative frequencies of monogenic variants might vary slightly among different populations, but the most frequent are mutations in LDLR [ 7 , 8 ].…”
Section: Monogenic Vs Polygenic Determinationmentioning
confidence: 99%
“…GRS is also used for the detection of so-called “polygenic FH” (see above), although FH was originally recognized as a monogenic disease. Currently, approximately 20% of clinically diagnosed FH cases are suggested to have the polygenic form of FH [ 6 , 70 ]. FH patients without monogenic causes have been shown to have a high GRS resulting from the contribution of several (usually 6–12) common LDL-C-raising SNPs.…”
Despite the rapid progress in diagnosis and treatment of cardiovascular disease (CVD), this disease remains a major cause of mortality and morbidity. Recent progress over the last two decades in the field of molecular genetics, especially with new tools such as genome-wide association studies, has helped to identify new genes and their variants, which can be used for calculations of risk, prediction of treatment efficacy, or detection of subjects prone to drug side effects. Although the use of genetic risk scores further improves CVD prediction, the significance is not unambiguous, and some subjects at risk remain undetected. Further research directions should focus on the “second level” of genetic information, namely, regulatory molecules (miRNAs) and epigenetic changes, predominantly DNA methylation and gene-environment interactions.
“…However, the FH diagnosis should be made only in the presence of the causative genetic defect (3). This is most often a point mutation in either the LDL receptor (LDLR), apolipoprotein B100 (APOB), or subtilisin-kexin type 9 proprotein convertase (PCSK9) genes (4). There is also the polygenic aspect, in which several cholesterol-rising gene modifications contribute to FH (1) occurrence, and also the disease being caused by copy number variations (CNVs).…”
Familial hypercholesterolemia (FH) manifested as atherosclerosis is a major cause of coronary heart disease. Different scoring systems based on clinical and paraclinical data are currently used, but the FH diagnosis should be made only in the presence of the causative genetic defect. In the present study, 12 symptomatic (previously diagnosed with atherosclerosis) and asymptomatic family members were investigated. Serum lipids were measured using commercial reagents. A genetic investigation was performed by Sanger sequencing using commercial reagents and custom primers, while copy number variations and a selected set of 40 point mutations were evaluated using in vitro diagnostic medical devices. For the investigated patients, serum lipids were within the reference range, due to the fact that the subjects were following lipid-lowering therapy, and smoking was the only identifiable additional risk factor. Four benign exon variants and three intron variants situated within the low-density lipoprotein cholesterol receptor gene were identified by Sanger sequencing. No copy number variations and none of the 40 investigated point mutations were determined. Although independently considered benign, the combined effect of the identified genetic conditions could be pathogenic under the influence of additional risk factors. Even in the presence of a diagnosis made using clinical scores, the molecular diagnosis is often challenging, attesting to the complexity of FH genetic etiology.
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