Liver transplantation in a subject with familial hypercholesterolemia carrying the homozygous p.W577R LDL-receptor gene mutation

2007 ◽  
Vol 22 (2) ◽  
pp. 180-184 ◽  
Author(s):  
Hartmut H-J. Schmidt ◽  
Uwe J.F. Tietge ◽  
Janine Buettner ◽  
Hannelore Barg-Hock ◽  
Gisela Offner ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Familial Hypercholesterolemia ◽  
Gene Mutation ◽  
Receptor Gene ◽  
Ldl Receptor

scholarly journals Increased production of VLDL apoB-100 in subjects with familial hypercholesterolemia carrying the same null LDL receptor gene mutation

2004 ◽  
Vol 45 (5) ◽  
pp. 866-872 ◽  
Author(s):  
André J. Tremblay ◽  
Benoît Lamarche ◽  
Isabelle L. Ruel ◽  
Jean-Charles Hogue ◽  
Jean Bergeron ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Gene Mutation ◽  
Receptor Gene ◽  
Ldl Receptor

Abstract 207: A Catalogue of the Pathogenic Mutations of LDL Receptor Gene in Japanese Familial Hypercholesterolemia

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Hayato Tada ◽  
Soichiro Usui ◽  
Masa-aki Kawashiri ◽  
Masayuki Takamura ◽  
Mariko Harada-shiba
Keyword(s):  
Familial Hypercholesterolemia ◽  
Gene Mutation ◽  
Receptor Gene ◽  
Ldl Receptor ◽  
Genetic Mutations ◽  
Single Mutation ◽  
Pathogenic Mutations ◽  
Cardiovascular Center ◽  
Center Research ◽  
Research Institute

Background: Familial hypercholesterolemia (FH), mainly caused by LDL receptor gene mutation is attracting a lot of attention associated with the development of novel therapies. However, rare mutations tend to be ethnicity-specific, hence, it is always difficult to determine pathogenicity of LDL receptor gene mutation in a single individual in a certain ethnicity. Currently, little data exist on the pathogenic mutations of LDL receptor in Japanese familial hypercholesterolemia (FH). Objective: We aimed to catalogue the pathogenic mutations of LDL receptor gene in the 2 major Japanese FH-care centers (Kanazawa University and National Cerebral and Cardiovascular Center Research Institute), where genetic testing of FH has been performed centrally upon requests from institutes all over Japan during more than past two decades. Methods: 796 FH subjects from 472 families who had nonsynonymous mutations in LDL receptor gene were included in this study. Genetic mutations were analyzed for mutations by Sanger sequencing as well as by multiplex ligation probe dependent amplification (MLPA) technique for large rearrangements. Pathogenic mutations were defined either as 1) protein truncated variants, 2) registered as pathogenic in Clinvar, or Human Gene Mutation Database (HGMD), or meet the criteria of American College of Medical Genetics and Genomics (ACMG) guideline, or 3) CADD-score > 10. Results: We found 138 different mutations. Among them, 132 mutations were considered as pathogenic, including 19 large rearrangement mutations. Whereas, 6 missense mutations were classified as variants of unknown significance (VUS). A single mutation accounted for as much as 41 % of the FH subjects recruited from Kanazawa University mainly due to founder gene effect, whereas, many singleton mutations were found from National Cerebral and Cardiovascular Center Research Institute located in Osaka. Conclusions: We provided the largest catalogue of pathogenic mutations of LDL receptor gene in Japanese FH. This could aid to determine the pathogenicity of the LDL receptor genetic mutations not only in Japanese but also in other ethnicities.

scholarly journals Long-Distance PCR-based Screening for Large Rearrangements of the LDL Receptor Gene in Korean Patients with Familial Hypercholesterolemia

1999 ◽  
Vol 45 (9) ◽  
pp. 1424-1430 ◽  
Author(s):  
Sung Han Kim ◽  
Ji Hyun Bae ◽  
Jae Jin Chae ◽  
Un Kyung Kim ◽  
Seong-Joon Choe ◽  
...  
Keyword(s):  
Sequence Analysis ◽  
Familial Hypercholesterolemia ◽  
Receptor Gene ◽  
Blot Hybridization ◽  
Screening Method ◽  
Ldl Receptor ◽  
Southern Blot Hybridization ◽  
Long Distance ◽  
Large Rearrangements ◽  
Long Distance Pcr

Abstract Background: The LDL receptor is a cell-surface protein that regulates plasma cholesterol by specific uptake of LDL particles from the blood circulation. Familial hypercholesterolemia (FH) results from defective catabolism of LDL, which is caused by mutations in the LDL-receptor gene. Methods: For the rapid and reliable detection of large rearrangements in the LDL-receptor gene, we established a screening method based on long-distance PCR as an alternative to Southern-blot hybridization. Using long-distance PCR, 45 unrelated Korean subjects heterozygous for FH were screened to assess the frequency and nature of major structural rearrangements in the LDL-receptor gene. Results: Two different deletion mutations, FH6 (same type as FH3 and FH311) and FH 32, were detected in four families by long-distance PCR. Detailed restriction mapping and sequence analysis showed that FH6 was a 5.71-kb deletion extending from intron 8 to intron 12 and that FH32 was a 2-kb deletion extending from intron 6 to intron 7. Sequence analysis for the breakpoints of all deletions detected in Korean FH patients showed that only the left arms of the Alu repetitive sequences were involved in the deletion event. Conclusions: The screening method based on long-distance PCR provides a powerful strategy for the detection of large rearrangements in the LDL-receptor gene and is a rapid and reliable screening alternative to Southern-blot hybridization.

scholarly journals Familial Hypercholesterolemia: Three “under” (Understood, Underdiagnosed, and Undertreated) Disease

2021 ◽  
Author(s):  
Vladimir O. Konstantinov
Keyword(s):  
Familial Hypercholesterolemia ◽  
Time Course ◽  
Ldl Cholesterol ◽  
Genetic Disorders ◽  
Receptor Gene ◽  
Ldl Receptor ◽  
Hdl Cholesterol ◽  
Blood Cholesterol ◽  
Healthy Population ◽  
Loss Of Function

Familial hypercholesterolemia (FH) is one of the most prevalent genetic disorders leading to premature atherosclerosis and coronary heart disease. The main cause of FH is a mutation in the LDL-receptor gene that leads to loss of function of these receptors causing high levels of blood cholesterol. The diagnosis of FH is not very easy. Wide screenings are needed to reveal high levels of LDL cholesterol among “healthy” population. If the patient has MI or stroke at an early age, high levels of LDL cholesterol, and tendon xanthomas, the diagnosis of FH becomes much more clear. Genetic testing is a gold standard in the diagnosis of FH. There are several factors, influencing the time course of FH. Smoking males with low levels of HDL cholesterol have an extremely higher risk of death than nonsmoking females with high HDL cholesterol. Management of FH includes low cholesterol diet, statin and ezetimibe treatment, PCSK inhibitors, and LDL aphaeresis. Early and effective treatment influences much the prognosis in FH patients.

Abstract 50: A Phase I Clinical Trial Evaluating the Safety of With Allogeneic Adipose Tissue-derived Multilineage Progenitor Cells-transplantation Therapy in Homozygous Familial Hypercholesterolemia Patients

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Masahiro Koseki ◽  
Shizuya Yamashita
Keyword(s):  
Clinical Trial ◽  
Liver Transplantation ◽  
Adipose Tissue ◽  
Progenitor Cells ◽  
Familial Hypercholesterolemia ◽  
Ldl Cholesterol ◽  
Ldl Receptor ◽  
Ldl Apheresis ◽  
Definitive Therapy ◽  
Transplantation Therapy

Familial hypercholesterolemia (FH) is an inherited disorder, mainly caused by defects in low-density lipoprotein (LDL) receptor gene. The patients are characterized by high LDL cholesterol levels in the blood and premature cardiovascular disease. Although most of heterozygous FH patients are usually treated with statin, ezetimibe and bile acid sequestrants, homozygous FH patients are resistant to drug therapy. Therefore, in Japan, many of homozygous FH patients are treated by LDL-apheresis. LDL-apheresis is a great procedure to remove LDL cholesterol from the blood and contribute to improve prognosis of homozygous FH patients. However, the effect of removing LDL cholesterol is temporary and still not enough. As a definitive therapy, liver transplantation therapy could be one of options to recover LDL receptor, but donor is limited in Japan. Therefore, based on the increase of the evidence about the safety of mesenchymal stem cells and percutaneous transhepatic portal approach in islet transplantation, we have developed a cell transplantation therapy with allogeneic adipose tissue-derived multilineage progenitor cells (ADMPCs), as an alternative treatment instead of liver transplantation. Our group has already proved that xenogenic transplantation of human ADMPCs into Watanabe heritable hyperlipidemic rabbits resulted in significant reductions in total cholesterol, and the reductions were observed within 4 weeks and maintained for 12 weeks. These results suggested that hADMPC transplantation could correct the metabolic defects and be a novel therapy for inherited liver diseases. Here, we report a protocol for the first-in-human clinical trial, which has been approved by the institutional review board and Ministry of Health, Labour and Welfare, Japan.

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