The vast majority of fh patients carry a mutation in the coding region of ldlr, apob, or pcsk9. Genetics of familial hypercholesterolemia springerlink. Autosomal dominant inheritance means one copy of an altered gene in each cell is sufficient to cause the disorder. Familial hypercholesterolemia resulting from mutations in the ldlr, apob, or pcsk9 gene have an autosomal dominant pattern of inheritance. The familial hypercholesterolemias fh are a group of genetic defects resulting in severe elevations of blood cholesterol levels. Cholesterol is a waxy, fatlike substance that is produced in the body and obtained from foods that come from animals particularly egg yolks, meat, poultry, fish, and dairy products. Screening for genetic mutations in ldlr gene with familial. Eight mutations in lowdensity lipoprotein receptor ldlr gene were. Familial hypercholesterolemia is a condition characterized by very high levels of cholesterol in the blood due to mutations in the ldlr gene. We use cookies to make interactions with our website easy and meaningful, to better understand the use of our services, and to tailor advertising. Familial hypercholesterolemia is an inherited condition characterized by very high levels of cholesterol in the blood.
Homozygous familial hypercholesterolemia familial hypercholesterolemia is an inherited disease that results in exceptionally high levels of low density lipoprotein cholesterol ldlc from birth. Ldlr gene, which abolish receptornegative or greatly reduce. Class ii ldlr mutations result in a misfolded ldlr retained in the endoplasmic reticulum er. A retrospective on functional characterization of ldlr variants asier benitovicente, kepa b. The low density lipoprotein ldl receptor is a cell surface transmembrane protein that mediates the uptake and lysosomal degradation of plasma ldl, thereby providing cholesterol to cells. Hasanato5, sarar mohamed6, waleed tamimi7 and imran ali khan1 1department of clinical laboratory sciences, college of applied medical sciences, king saud. Although relatively few identified variants in apob and pcsk9 contribute to fh, ldlr is known to harbor more than 1,600 reported variants distributed throughout the coding region. We have developed a model of fh class ii and crisprcorrected induced pluripotent stem cells ipsc capable of.
Lowdensity lipoprotein receptor ldlr associated familial hypercholesterolemia fh is the most frequent mendelian disorder and is a major risk factor for the. Familial hypercholesterolemia fh is an inherited disorder characterized by high plasma ldlc lowdensity lipoproteincholesterol levels. A japanese case of familial hypercholesterolemia with a. Familial hypercholesterolemia fh is a common and serious dominant genetic disease and its main pathogenic gene is the lowdensity lipoprotein receptor ldlr gene. Genetic analysis of familial hypercholesterolemia in asian. We collected and analyzed the clinical data of the proband in the case and her imme. We collected and analyzed the clinical data of the proband in the case and her immediate family members, and detected the ldlr, proprotein convertase subtilisinkexin type 9 pcsk. Screening of small populations where at least one homozygous hofh patient has been identified may be a proper approach for detecting fh patients. Ldlr defects lead to familial hypercholesterolemia fh, a common autosomal semidominant disease affecting 1 in 500 individuals and characterized by cholesterol deposit in the skin, tendons, and coronary arteries atherosclerosis. The homozygous form of the disease is when there are 2 faulty copies of the genes responsible for cholesterol production and removal. Plasma levels of lowdensity lipoprotein cholesterol ldlc are positively correlated with the risk of atherosclerosis. Familial hypercholesterolemia fh refers to high cholesterol that runs in a family.
A novel mechanism causing familial hypercholesterolemia. A mutation in a single copy of the ldlr gene inherited from either parent is known to cause familial hypercholesterolemia fh, which is a hereditary disorder associated with very high. Genetic studies have established the association of fh and variants in three genes. Ldlr, which is the receptor for ldlc, plays a critical role in cholesterol transport and clearance from the plasma to the cytoplasm, and its functional insufficiency can lead to familial hypercholesterolemia fh and increase the risk of cvd. Recent origin and spread of a common lithuanian mutation. The distribution and characteristics of ldl receptor. Pdf familial hypercholesterolemia fh is most commonly caused by mutations in the ldl receptor ldlr, which is responsible for hepatic clearance of. Lowdensity lipoprotein ldl receptor ldlr mutations are the primary cause of familial hypercholesterolemia fh. Analysis of publicly available ldlr, apob, and pcsk9. Herein, we identified an fh patient presenting novel compound heterozygote mutations r410s and. In 95% of patients, homozygous familial hypercholesterolemia is due to mutations in lowdensity lipoprotein receptor ldlr gene, which abolish receptor. Although the term fh has, in the past, been used to refer speci. Analysis of publicly available ldlr, apob, and pcsk9 variants associated with familial hypercholesterolemia. Goldstein were awarded the 1985 nobel prize in physiology or medicine for their identification of ldl r and its relation to cholesterol metabolism and familial hypercholesterolemia.
Familial hypercholesterolemia fh is an autosomal dominant disorder resulting in elevated plasma lowdensity lipoprotein cholesterol ldlc. Familial hypercholesterolemia fh is a common inherited disorder that causes. A japanese case of familial hypercholesterolemia with a novel mutation in the ldlr gene. The ldlrko rabbits should be a useful rabbit model of human familial hypercholesterolemia fh for the simulations of human primary hypercholesterolemia and such models would allow more exact research into cardiocerebrovascular disease. Cys681x mutation in hypercholesterolemic lebanese families and identify other less frequent mutations in the ldlr gene causing fh. Spectrum of lowdensity lipoprotein receptor ldlr mutations in a. Pdf a japanese case of familial hypercholesterolemia. Hamsters, like humans, have the cholesteryl ester transfer protein, intestineonly apob editing and low hepatic cholesterol synthesis. Uribe, shifa jebari, unai galiciagarcia, helena ostolaza and cesar martin. Mutation spectrum of ldlr in familial hypercholesterolemia patients. Ldlr acts as a receptor for the hiv1 tat protein in neurons and mediates its internalization. Current status of familial hypercholesterolemia in china frontiers. The prevalence of fh is estimated to be approximately, 1 in 200 and 1 in 170,000 among heterozygotes and homozygotes, respectively 1.
Familial hypercholesterolemia genetics home reference nih. Familial hypercholesterolemia genetic and rare diseases. These cases are associated with an increased risk of early heart disease, typically beginning in a persons forties or fifties. People with hypercholesterolemia have a high risk of developing a form of heart disease called coronary artery disease, as well as health problems related to the buildup of excess cholesterol in other tissues e. Familial hypercholesterolemia fh is an autosomaldominant inherited condition that causes very high levels of cholesterol in the blood, mainly lowdensity lipoprotein ldl cholesterol ldlc, which leads to an increased incidence of premature cardiovascular disease cvd.
Fh often leads to premature chd and is one of the most common diseases of lipid metabolism. Familial hypercholesterolemia fh is a genetic disorder characterized by elevated lowdensity lipoprotein ldl cholesterol and premature cardiovascular disease, with a prevalence of approximately 1 in 200500 for heterozygotes in north america and europe. Familial hypercholesterolemia fh is an autosomal dominant disorder of lipoprotein. Molecular genetics of the ldl receptor gene in familial. Familial hypercholesterolemia with two mutations in ldlr. The genetic spectrum of familial hypercholesterolemia fh nature. Regulation of the ldl receptor in familial hypercholesterolemia. Ldlr gene in a patient with homozygous familial hypercholesterolemia. Familial hypercholesterolemia fh is an autosomal dominant disease characterized by extremely high blood cholesterol levels, which leads to premature cardiovascular disease cd. Individuals with this disease are unable to uptake lowdensity lipoprotein ldl, a specific type of cholesterol, from the blood because of certain defective proteins involved in the cholesterol clearance pathway. Genetic screening to improve the diagnosis of familial. Endoplasmic reticulum quality control of ldlr variants associated with familial hypercholesterolemia praseetha kizhakkedath1, anne john1, buthaina k.
The purpose of this study was to determine the origin, age, and population distribution of g197del, as well as to explore environmental and genetic effects on. Homozygous familial hypercholesterolemia hofh is an inherited condition which leads to extremely elevated levels of lowdensity lipoprotein ldl cholesterol. Familial hypercholesterolemia fh is a genetic disorder of lipoprotein metabolism characterized by high plasma concentrations of lowdensity lipoprotein cholesterol ldlc, tendon xanthomas, and increased risk of premature coronary heart disease. Familial hypercholesterolaemia fh is an autosomal dominant inherited disease characterised by increased lowdensity lipoprotein cholesterol ldlc levels. Variable expressivity and cooccurrence of ldlr and ldlrap1 mutations in familial hypercholesterolemia. Endoplasmic reticulum quality control of ldlr variants. Regular paper screening for genetic mutations in ldlr gene with familial hypercholesterolemia patients in the saudi population khalid khalaf alharbi1, tarek s kashour2, wejdan alhussaini1,3, may salem nbaheen3,4, rana m.
We report a case of familial hypercholesterolemia fh with two mutations in low density lipoprotein receptor ldlr gene and speculate the correlation between the newly discovered mutation type of ldlr gene and fh. Familial hypercholesterolemia fh is an autosomal dominant disease characterized by an increased ldlcholesterol ldlc serum concentration and premature cardiovascular disease. Impact of ldlr mutations like most genes, each person has two copies of the ldlr gene. Genetic causes of monogenic heterozygous familial hypercholesterolemia. Characterization of the effects of familial hypercholesterolemia. Ldl receptor ldlr, apolipoprotein b apob, and proprotein convertase subtilisinkexin type 9 pcsk9. Mutations disrupting the function of this receptor produce autosomal dominant familial hypercholesterolemia fh. Pdf compound heterozygous ldlr variant in severely. Ali1,3 1 department of pathology, college of medicine and health sciences, united arab emirates university, alain, united arab emirates. Familial hypercholesterolemia fh is an inherited dys lipidemia characterized by a lifelong exposure to elevated. Patients with familial hypercholesterolemia have high levels of ldl in the blood and exhibit increased rates of.
Familial hypercholesterolemia fh is a codominant genetic disorder, with an estimated worldwide prevalence of 1 in 200 to 250 for heterozygous fh. Apob known familial mutation 81403 pcsk9 known familial mutation 81403 ldlr sequencing 81406 ldlr deletionduplication 81405 apob targeted mutation analysis 81401 apob sequencing 81479 pcsk9 sequencing 81406 what is familial hypercholesterolemia definition familial hypercholesterolemia fh is a genetic disorder characterized by very high. Monogenic fh is largely attributed to mutations in the ldlr, apob, and pcsk9 genes. Ldlr variant databases and familial hypercholesterolemia. The functionality of four novel variants within the ldlr 5. G197del is the most prevalent ldl receptor ldlr mutation causing familial hypercholesterolemia fh in ashkenazi jew aj individuals. Unlike fh patients, heterozygous ldlr knockout ko mice do not show a dominant fh trait.
Homozygous familial hypercholesterolemia is a rare clinical phenotype with a variable expression, which is characterized by extremely elevated plasma lowdensity lipoprotein ldl, tendon and skin xanthomas, and a progressive atherosclerosis. Use of nextgeneration sequencing to detect ldlr gene copy. Familial hypercholesterolemia fh is an autosomal dominant genetic disease caused mainly by ldl receptor ldlr gene mutations. Familial hypercholesterolemia fh is an inherited disorder characterized by elevated serum low density lipoprotein ldl cholesterol levels. We set out to identify the culprit genetic defect in a large family with clinical fh, in whom no mutations. Functional mutation in the ldlr, apob, or pcsk9 gene 8 interpretation total definite familial hypercholesterolemia 8 probable familial hypercholesterolemia 68 possible familial hypercholesterolemia 35 unlikely familial hypercholesterolemia on april 11, 2020. Validation of ldlr activity as a tool to improve genetic diagnosis of familial hypercholesterolemia. Genetic testing familial hypercholesterolemia fh apob. Most people with familial hypercholesterolemia inherit one altered copy of the ldlr gene from an affected parent and one normal copy of the gene from the other parent. Update on guidelines for management of familial hypercholesterolemia.
Dominant mutations in ldlr can affect ligand binding or intracellular trafficking i. A complex rearrangement in the ldlr gene in a patient with. Finally, we show that pcsk9 might constitute a modifier gene in familial hypercholesterolemia by studying for the first time the impact. Read more about symptoms, diagnosis, treatment, complications, causes and prognosis. The ldlr gene also contains one of 27 snps associated with increased risk of coronary artery disease.
Xiaoqian zhang1,2, xi wang1, anli tong1, naishi li1, chongmei lu2. Ldlr cause familial hypercholesterolemia fh, a common. Familial hypercholesterolemia fh is an inherited disorder of lipoprotein metabolism characterized by elevated low density lipoprotein ldl. Homozygous familial hypercholesterolemia patients with. By age 50, approximately 45% of male and 20% of female fh patients suffer from coronary artery disease, a primary causative factor for chd goldstein et al. This causes an increased risk for early heart attack and stroke from high ldl cholesterol often called bad cholesterol. Test familial hypercholesterolemia via the ldlr gene. Genetically confirmed familial hypercholesterolemia in outpatients. The present study adds to the landscape of molecular heterogeneity of fh in bulgaria the frequency and molecular characteristics of large.
The genetic basis of familial hypercholesterolemia. Pdf ldlrgene therapy for familial hypercholesterolaemia. Case report a newlyfound homozygous mutation in the ldlr. Familial hypercholesterolemia is a common autosomal dominant disease associated with mutations in the gene for the lowdensity lipoprotein ldl receptor. More than different mutations in the ldl receptor gene ldlr result in familial hypercholesterolemia fh. Confirm a clinical diagnosis of familial hypercholesterolemia fh and allow early diagnosis in family members, thus promoting early intervention, which may prevent or repair atherosclerotic damage and lower the risk of coronary artery disease.
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