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1. Comparison of two polygenic risk score to identify non-monogenic primary hypocholesterolemias in a large cohort of Italian hypocholesterolemic subjects: Polygenic hypocholesterolemias

Author

Cefalu A. B., Spina R., Noto D., Rabacchi C., Giammanco A., Simone M. L., Brucato F., Scrimali C., Gueli-Alletti M. G., Barbagallo C. M., Tarugi P., Averna M, Cefalu A.B., Spina R., Noto D., Rabacchi C., Giammanco A., Simone M.L., Brucato F., Scrimali C., Gueli-Alletti M.G., Barbagallo C.M., Tarugi P., and Averna M

Subjects
Polygenic risk score, Mutation, Hypobetalipoproteinemia
Abstract

Background: Primary Hypobetalipoproteinemias (HBL) are a group of dominant and recessive monogenic genetic disorders caused by mutations in APOB, PCSK9, ANGPTL3, MTTP, Sar1b genes and characterized by plasma levels of total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (apoB) below the 5th percentile of the distribution in a given population. Mutations in the candidate genes account only for a small proportion of subjects with HBL suggesting a role for a polygenic contribution to the low cholesterol phenotype. Objective: To explore the complex genetic architecture of HBL we compared two polygenic risk scores in order to assess the role of the polygenic burden and the differences in the clinical phenotype between monogenic and polygenic HBL; we studied a cohort of 170 subjects with primary HBL referred over a 25-year period to 2 Italian reference centers have been studied. Methods: The genetic analyses have been based on: Sanger sequencing, in-house NGS customized panel and two scores, PRS1 and PRS2 for the polygenic burden. Results: Sixty 60 (35%) and 63 (37%) subjects had a monogenic and polygenic HBL respectively. LDL-C plasma levels were significantly lower in monogenic HBL (30.87 ± 3.12 mg/dl) compared with the non-monogenic HBL (42.80 ± 2.18 mg/dl) (p

Published
2022

2. Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)

Author

Vallejo-Vaz, A.J. Marco, M.D. Stevens, C.A.T. Akram, A. Freiberger, T. Hovingh, G.K. Kastelein, J.J.P. Mata, P. Raal, F.J. Santos, R.D. Soran, H. Watts, G.F. Abifadel, M. Aguilar-Salinas, C.A. Al-Khnifsawi, M. Alkindi, F.A. Alnouri, F. Alonso, R. Al-Rasadi, K. Al-Sarraf, A. Ashavaid, T.F. Binder, C.J. Bogsrud, M.P. Bourbon, M. Bruckert, E. Chlebus, K. Corral, P. Descamps, O. Durst, R. Ezhov, M. Fras, Z. Genest, J. Groselj, U. Harada-Shiba, M. Kayikcioglu, M. Lalic, K. Lam, C.S.P. Latkovskis, G. Laufs, U. Liberopoulos, E. Lin, J. Maher, V. Majano, N. Marais, A.D. März, W. Mirrakhimov, E. Miserez, A.R. Mitchenko, O. Nawawi, H.M. Nordestgaard, B.G. Paragh, G. Petrulioniene, Z. Pojskic, B. Postadzhiyan, A. Reda, A. Reiner, Ž. Sadoh, W.E. Sahebkar, A. Shehab, A. Shek, A.B. Stoll, M. Su, T.-C. Subramaniam, T. Susekov, A.V. Symeonides, P. Tilney, M. Tomlinson, B. Truong, T.-H. Tselepis, A.D. Tybjærg-Hansen, A. Vázquez-Cárdenas, A. Viigimaa, M. Vohnout, B. Widén, E. Yamashita, S. Banach, M. Gaita, D. Jiang, L. Nilsson, L. Santos, L.E. Schunkert, H. Tokgözoğlu, L. Car, J. Catapano, A.L. Ray, K.K. Schreier, L. Pang, J. Dieplinger, H. Hanauer-Mader, G. Desutter, J. Langlois, M. Mertens, A. Rietzschel, E. Wallemacq, C. Isakovic, D. Dzankovic, A.M. Obralija, J. Pojskic, L. Sisic, I. Stimjanin, E. Torlak, V.A. Jannes, C.E. Krieger, J.E. Pereira, A.C. Ruel, I. Asenjo, S. Cuevas, A. Pećin, I. Miltiadous, G. Panayiotou, A.G. Vrablik, M. Benn, M. Heinsar, S. Béliard, S. Gouni-Berthold, I. Hengstenberg, W. Julius, U. Kassner, U. Klose, G. König, C. König, W. Otte, B. Parhofer, K. Schatz, U. Schmidt, N. Steinhagen-Thiessen, E. Vogt, A. Antza, C. Athyros, V. Bilianou, E. Boufidou, A. Chrousos, G. Elisaf, M. Garoufi, A. Katsiki, N. Kolovou, G. Kotsis, V. Rallidis, L. Rizos, C. Skalidis, E. Skoumas, I. Tziomalos, K. Shawney, J.P.S. Abbaszadegan, M.R. Aminzadeh, M. Hosseini, S. Mobini, M. Vakili, R. Zaeri, H. Agar, R. Boran, G. Colwell, N. Crowley, V. Durkin, M. Griffin, D. Kelly, M. Rakovac-Tisdall, A. Bitzur, R. Cohen, H. Eliav, O. Ellis, A. Gavish, D. Harats, D. Henkin, Y. Knobler, H. Leavit, L. Leitersdorf, E. Schurr, D. Shpitzen, S. Szalat, A. Arca, M. Averna, M. Bertolini, S. Calandra, S. Tarugi, P. Erglis, A. Gilis, D. Nesterovics, G. Saripo, V. Upena-Roze, A. Elbitar, S. Jambart, S. Khoury, P.E. Gargalskaite, U. Kutkiene, S. Al-Khateeb, A. An, C.Y. Ismail, Z. Kasim, S. Ibrahim, K.S. Radzi, A.B.M. Kasim, N.A. Nor, N.S.M. Ramli, A.S. Razak, S.A. Muid, S. Rosman, A. Sanusi, A.R. Razman, A.Z. Nazli, S.A. Kek, T.L. Azzopardi, C. Aguilar Salinas, C.A. Galán, G. Rubinstein, A. Magaña-Torres, M.T. Martagon, A. Mehta, R. Wittekoek, M.E. Isara, A.R. Obaseki, D.E. Ohenhen, O.A. Holven, K.B. Gruchała, M. Baranowska, M. Borowiec-Wolny, J. Gilis-Malinowska, N. Michalska-Grzonkowska, A. Pajkowski, M. Parczewska, A. Romanowska-Kocejko, M. Stróżyk, A. Żarczyńska-Buchowiecka, M. Kleinschmidt, M. Alves, A.C. Medeiros, A.M. Ershova, A. Korneva, V. Kuznetsova, T. Malyshev, P. Meshkov, A. Rozhkova, T. Popovic, L. Lukac, S.S. Stosic, L. Rasulic, I. Lalic, N.M. Chua, T.S.J. Ting, S.P.L. Raslova, K. Battelino, T. Cevc, M. Jug, B. Kovac, J. Podkrajsek, K.T. Sustar, U. Trontelj, K.J. Marais, D. Isla, L.P. Martin, F.J. Charng, M.-J. Chen, P.-L. Kayikçioglu, M. Dell’oca, N. Fernández, G. Ressia, A. Reyes, X. Zelarayan, M. Alieva, R.B. Hoshimov, S.U. Nizamov, U.I. Kurbanov, R.D. Lima-Martínez, M.M. Nguyen, M.-N.T. Do, D.-L. Kim, N.-T. Le, T.-T. Le, H.-A.

Abstract

Background and aims: Management of familial hypercholesterolaemia (FH) may vary across different settings due to factors related to population characteristics, practice, resources and/or policies. We conducted a survey among the worldwide network of EAS FHSC Lead Investigators to provide an overview of FH status in different countries. Methods: Lead Investigators from countries formally involved in the EAS FHSC by mid-May 2018 were invited to provide a brief report on FH status in their countries, including available information, programmes, initiatives, and management. Results: 63 countries provided reports. Data on FH prevalence are lacking in most countries. Where available, data tend to align with recent estimates, suggesting a higher frequency than that traditionally considered. Low rates of FH detection are reported across all regions. National registries and education programmes to improve FH awareness/knowledge are a recognised priority, but funding is often lacking. In most countries, diagnosis primarily relies on the Dutch Lipid Clinics Network criteria. Although available in many countries, genetic testing is not widely implemented (frequent cost issues). There are only a few national official government programmes for FH. Under-treatment is an issue. FH therapy is not universally reimbursed. PCSK9-inhibitors are available in ∼2/3 countries. Lipoprotein-apheresis is offered in ∼60% countries, although access is limited. Conclusions: FH is a recognised public health concern. Management varies widely across countries, with overall suboptimal identification and under-treatment. Efforts and initiatives to improve FH knowledge and management are underway, including development of national registries, but support, particularly from health authorities, and better funding are greatly needed. © 2018 Elsevier B.V.

Published
2018

3. Evaluation of the performance of Dutch Lipid Clinic Network score in an Italian FH population: The LIPIGEN study

Author

Casula, M. a., B, Be, Olmastroni, E. a., Pirillo, A. c., Catapano, D, A. L. b., D, Jemail, Author, Lipigen, Group, Averna, M. g., Bertolini, S. h., Calandra, S. i., Tarugi, P. i., Pellegatta, F. k., Angelico, F. f., Bartuli, A. l., Biasucci, G. m., Biolo, G. n., Bonanni, L. o., Bonomo, K. p., Borghi, C. q., Bossi, A. C. r., Branchi, A. s., Carubbi, F. t., Cipollone, F. u., Citroni, N. v., Federici, M. w., Ferri, C. x., Fiorenza, A. M. y., Giaccari, A. z., Giorgino, Aa, F., Guardamagna, Ab, O., Iannuzzi, Ac, A., Iughetti, Ad, L., Lupattelli, Ae, G., Lupi, Af, A., Mandraffino, Giuseppe, Ag, G., Marcucci, Ah, R., Maroni, Ai, L., Miccoli, Aj, R., Mombelli, Ak, G., Muntoni, Al, S., Pecchioli, Am, V., Pederiva, An, C., Pipolo, Ao, A., Pisciotta, Ap, L., Pujia, Aq, A., Purrello, Ar, F., Repetti, As, E., Rubba, At, P., Sabbà, Au, C., Sampietro, Av, T., Sarzani, Aw, R., Tagliabue, M. P., Ax, Trenti, Ay, C., Vigna, G. B., Az, Werba, J. P., Ba, Zambon, Bb, S., Zenti, M. G., Bc, Minicocci, I. f., Noto, D. g., Fortunato, Bd, G., Banderali, An, G., Benso, Ax, A., Bigolin, Bb, P., Bonora, Bc, E., Bruzzi, Ad, P., Bucci, M. u., Buonuomo, P. S. l., Capra, M. E. m., Cardolini, I. w., Cefalù, B. g., Cervelli, N. x., Chiariello, Ac, G., Cocci, Aw, G., Colombo, E. y., Cremonini, A. L., Ap, D'Addato, S. q., D'Erasmo, L. f., Dal, Pino, Av, B., Sanctis, De, Ab, L., Vita, De, Ao, E., Del, Ben, M. f., Costanzo, Di, A. f., Taranto, Di, M. D., Bd, Fasano, Ay, T., Gentile, As, L., At, M., Ghirardello, Az, O., Grigore, L. k., Lussu, Al, M., Meregalli, G. r., Moffa, S. z., Montalcini, Aq, T., Morgia, Nascimbeni, F. t., Pasta, A. h., Pavanello, Ak, C., Saitta, Antonino, Ag, A., Scicali, Ar, R., Siepi, Ae, D., Spagnolli, W. v., Spina, R. g., Sticchi, Ah, E., Suppressa, Au, P., Vigo, Ba, L., Vinci, P. n., Manzato, Bf, E., Tragni, Be, E., Zampoleri, Bg, V., Casula, Manuela, Olmastroni, Elena, Pirillo, Angela, Catapano, Alberico Luigi, Arca, Marcello, Averna, Maurizio, Bertolini, Stefano, Calandra, Sebastiano, Tarugi, Patrizia, Pellegatta, Fabio, Angelico, Francesco, Bartuli, Andrea, Biasucci, Giacomo, Biolo, Gianni, Bonanni, Luca, Bonomo, Katia, Borghi, Claudio, Bossi, Antonio Carlo, Branchi, Adriana, Carubbi, Francesca, Cipollone, Francesco, Citroni, Nadia, Federici, Massimo, Ferri, Claudio, Fiorenza, Anna Maria, Giaccari, Andrea, Giorgino, Francesco, Guardamagna, Ornella, Iannuzzi, Arcangelo, Iughetti, Lorenzo, Lupattelli, Graziana, Lupi, Alessandro, Mandraffino, Giuseppe, Marcucci, Rossella, Maroni, Lorenzo, Miccoli, Roberto, Mombelli, Giuliana, Muntoni, Sandro, Pecchioli, Valerio, Pederiva, Cristina, Pipolo, Antonio, Pisciotta, Livia, Pujia, Arturo, Purrello, Francesco, Repetti, Elena, Rubba, Paolo, Sabbà, Carlo, Sampietro, Tiziana, Sarzani, Riccardo, Tagliabue, Milena Paola, Trenti, Chiara, Vigna, Giovanni Battista, Werba, Josè Pablo, Zambon, Sabina, Zenti, Maria Grazia, Minicocci, Ilenia, Noto, Davide, Fortunato, Giuliana, Banderali, Giuseppe, Benso, Andrea, Bigolin, Paola, Bonora, Enzo, Bruzzi, Patrizia, Bucci, Marco, Buonuomo, Paola Sabrina, Capra, Maria Elena, Cardolini, Iri, Cefalù, Baldassarre, Cervelli, Nazzareno, Chiariello, Giuseppe, Cocci, Guido, Colombo, Emanuela, Cremonini, Anna Laura, D'Addato, Sergio, D'Erasmo, Laura, Dal Pino, Beatrice, De Sanctis, Luisa, De Vita, Emanuele, Del Ben, Maria, Di Costanzo, Alessia, Di Taranto, Maria Donata, Fasano, Tommaso, Gentile, Luigi, Gentile, Marco, Ghirardello, Omar, Grigore, Liliana, Lussu, Milena, Meregalli, Giancarla, Moffa, Simona, Montalcini, Tiziana, Morgia, Valeria, Nascimbeni, Fabio, Pasta, Andrea, Pavanello, Chiara, Saitta, Antonino, Scicali, Roberto, Siepi, Donatella, Spagnolli, Walter, Spina, Rossella, Sticchi, Elena, Suppressa, Patrizia, Vigo, Lorenzo, Vinci, Pierandrea, Manzato, Enzo, Tragni, Elena, Zampoleri, Veronica, D'addato, Sergio, D'erasmo, Laura, Casula, M, Olmastroni, E, Pirillo, A, Catapano, A, Averna, M, Noto, D, Cefalu, B, and Spina, R

Subjects
Male, Settore MED/09 - Medicina Interna, Genetic testing, Predictive Value of Test, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Decision Support Technique, 0302 clinical medicine, Retrospective Studie, Risk Factors, Cardiovascular Disease, Genetic Marker, Prospective Studies, 030212 general & internal medicine, Age of Onset, Prospective cohort study, education.field_of_study, medicine.diagnostic_test, Middle Aged, Dutch Lipid Clinic Network score, Adult, Biomarkers, Cardiovascular Diseases, Cholesterol, LDL, Female, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Humans, Hyperlipoproteinemia Type II, Italy, Phenotype, Predictive Value of Tests, Reproducibility of Results, Retrospective Studies, Risk Assessment, Decision Support Techniques, Mutation, 3. Good health, Cholesterol, Cardiology and Cardiovascular Medicine, Human, medicine.medical_specialty, Population, Reproducibility of Result, Physical examination, LDL, 03 medical and health sciences, Internal medicine, medicine, First-degree relatives, education, business.industry, Risk Factor, Settore MED/13 - ENDOCRINOLOGIA, Biomarker, medicine.disease, Missing data, Dutch Lipid Clinic Network score, Familial hypercholesterolemia, Genetic testing, Prospective Studie, Age of onset, business
Abstract

Background and aims Familial hypercholesterolemia (FH) is an inherited disorder characterized by high levels of blood cholesterol from birth and premature coronary heart disease. Thus, the identification of FH patients is crucial to prevent or delay the onset of cardiovascular events, and the availability of a tool helping with the diagnosis in the setting of general medicine is essential to improve FH patient identification. Methods This study evaluated the performance of the Dutch Lipid Clinic Network (DLCN) score in FH patients enrolled in the LIPIGEN study, an Italian integrated network aimed at improving the identification of patients with genetic dyslipidaemias, including FH. Results The DLCN score was applied on a sample of 1377 adults (mean age 42.9 ± 14.2 years) with genetic diagnosis of FH, resulting in 28.5% of the sample classified as probable FH and 37.9% as classified definite FH. Among these subjects, 43.4% had at least one missing data out of 8, and about 10.0% had 4 missing data or more. When analyzed based on the type of missing data, a higher percentage of subjects with at least 1 missing data in the clinical history or physical examination was classified as possible FH (DLCN score 3–5). We also found that using real or estimated pre-treatment LDL-C levels may significantly modify the DLCN score. Conclusions Although the DLCN score is a useful tool for physicians in the diagnosis of FH, it may be limited by the complexity to retrieve all the essential information, suggesting a crucial role of the clinical judgement in the identification of FH subjects.

Published
2018

5. FUNCTIONAL CHARACTERIZATION OF NOVEL AMINO ACID VARIANTS IN APOB IN FAMILIAL HYPOBETALIPOPROTEINEMIA

Author

Magnolo, AL, Pinotti, E, Di Leo, E, Yao, Z, Tarugi, P., VALENTI, Vincenza, CEFALU', Angelo Baldassare, AVERNA, Maurizio, Magnolo, AL, Pinotti, E, Di Leo, E, Valenti, V, Cefalù, AB, Yao, Z, Averna, M, and Tarugi, P

Subjects
Settore MED/09 - Medicina Interna, missense variants, FHBL
Abstract

Introduction. Familial Hypobetalipoproteinemia (FHBL) is a codominant disorder characterized by reduced levels of LDL and apolipoprotein B (apoB) in plasma. In approximately 50% of FHBL cases is due to mutations in APOB gene resulting in truncated apoBs of various size. Only a few missense mutations have been reported so far as the cause of FHBL. In vitro studies have shown that these mutations induce retention of the mutant apoB in the endoplasmic reticulum and impair the secretion of apoB-containing lipoproteins. We identi ed two novel amino acid variants (Thr26-27del and Tyr102Cys) located in the N-terminal 1000 amino acids of mature apoB in two hypocholesterolemic blood donors. Methods. To investigate the functional effect of these variants we constructed plasmids containing human apoB-48 cDNAs harbouring the novel mutations. Rat hepatoma cells (McA-RH7777) were transiently and stably transfected with wild-type or the mutant forms of human apoB-48. The secretion ef ciency of human apoB- 48 was determined by immunoblotting with human anti-apoB and the incorporation of apoB into medium lipoproteins. Immunocytochemistry was used to monitor the intracellular localization of the mutant proteins. The post-translational stability and the intracellular degradation pathways of mutant apoB-48 was evaluated.Results and Conclusions. The mutation Tyr102Cys had no effect on apoB-48 secretion. The mutant apoB-48-Thr26-27del almost entirely abolished the secretion of apoB-48 and apoB-containing lipoproteins in the medium, suggesting that the deletion of two amino acids alters the structure of the beta-barrel (the rst 267 amino acids) of N-terminal domain of apoB. This mutant apoB-48 appears to be retained in endoplasmic reticulum. The addiction of a proteasome inhibitor partially blocked the decay of cellular apoB-48-Thr26-27del suggesting that a signi cant proportion of the mutant protein was degraded by the proteasomal pathway. The role of autophagy in the degradation of the mutant apoB was excluded.

Published
2013

6. A NOVEL APOB MUTATION IDENTIFIED BY EXOME SEQUENCING COSEGREGATES WITH STEATOSIS, LIVER CANCER AND HYPOCHOLESTEROLEMIA

Author

SPINA, Rossella, CEFALU', Angelo Baldassare, ALTIERI, Grazia Ida, VALENTI, Vincenza, FAYER, Francesca, PALESANO, Ornella, AVERNA, Maurizio, Pirruccello, JP, Noto, D, Gabriel, S, Gupta, N, Tarugi, P, Kathiresan, S, Spina, R, Cefalù AB, Pirruccello, JP, Altieri, GI, Noto, D, Gabriel, S, Valenti, V, Gupta, N, Fayer, F, Palesano, O, Tarugi, P, Kathiresan, S, and Averna, M

Subjects
Settore MED/09 - Medicina Interna, FHBL, HCC, fatty liver
Abstract

Objective. In familial hypobetalipoproteinemia (FHBL), fatty liver is a characteristic feature, and there are several reports of associated cirrhosis and hepatocarcinoma. We investigated a large kindred in which low-density lipoprotein (LDL) cholesterol, fatty liver and hepatocarcinoma displayed an autosomal dominant pattern of inheritance. Approach and Results. The proband was a 25 year-old female with low plasma cholesterol and hepatic steatosis. Low plasma levels of total cholesterol and fatty liver were observed in 10 more family members; 1 member was affected by liver cirrhosis and four more subjects died of either hepatocarcinoma or carcinoma on cirrhosis. To identify the causal mutation in this family, we performed exome sequencing in two participants with hypocholesterolemia and fatty liver. Approximately 22,400 single nucleotide variants were identi- ed in each sample. After variant ltering, 300 novel shared variants remained. A nonsense variant, p.K2240X due to an A>T mutation in exon 26 of APOB (c.6718A>T) was identi ed and this variant was con rmed by Sanger sequencing. The gentotypic analysis of 16 family members in total showed that this mutation segregated with the low cholesterol trait. In addition, genotyping of the PNPLA3 p.I148M did not show signi cant frequency differences between carriers and non-carriers of the c.6718A>T APOB gene mutation. Conclusions. We used exome sequencing to discover a novel nonsense mutation in exon 26 of APOB (p.K2240X) responsible for low cholesterol and fatty liver in a large kindred. This mutation may also be responsible for cirrhosis and liver cancer in this family.

Published
2013

7. FUNCTIONAL EFFECT OF NOVEL AMINO ACID VARIANTS OF APOLIPOPROTEIN B IN FAMILIAL HYPOBETALIPOPROTEINEMIA

Author

Magnolo, AL, Fancello, T, Pinotti, E, Tarugi, P., VALENTI, Vincenza, CEFALU', Angelo Baldassare, AVERNA, Maurizio, Magnolo, AL, Fancello, T, Pinotti, E, Valenti, V, Cefalù, AB, Averna, M, and Tarugi, P

Subjects
missense mutations, Settore MED/09 - Medicina Interna, FHBL
Abstract

Introduction. Familial Hypobetalipoproteinemia (FHBL) is a codominant disorder characterized by reduced plasma levels of LDL-C and apolipoprotein (apo) B. In 50% of cases FHBL is due to mutations in APOB gene resulting in truncated apoBs of various size. Some mutations in APOB gene resulting in non-conservative amino acid substitutions were reported to cause FHBL. In vitro, these mutations induce the retention of the mutant apoB in the endoplasmic reticulum (ER) and impair the secretion of apoB-containing lipoproteins. In two FHBL subjects we identified two novel amino acid variants (Thr26_27delinsAsn and Tyr102Cys) located in the N-terminal 1000 amino acids of mature apoB. Methods. To investigate the functional effect of these mutations we constructed plasmids containing human apoB-48 cDNAs harbouring the mutations. McA-RH7777 rat hepatoma cells were transiently and stably transfected with wild type or mutant human apoB-48. The secretion efficiency of human apoB-48 was determined by immunoblotting. To evaluate whether the mutant apoB- 48 was able to form apoB-containing lipoproteins, the incubation media were ultracentrifuged to separate the lipoprotein classes. Immunocytochemistry was used to assess the intracellular localization of the mutant proteins. Results. The mutation Thr26_27delinsAsn strongly reduces the secretion of apoB-48 from the transfected cells. The mutant apoB- 48 appears to be retained in ER as demonstrated by the confocal images showing co-localization of the mutant apoB with the ER marker. In stably transfected cells the defect of mutant apoB-48 secretion was confirmed by the absence of apoB-48 containing lipoproteins in the medium. These observations suggest that Thr26_27delinsAsn alters the structure of the beta-barrel of N-terminal domain of apoB (the first 267 amino acids of mature protein) preventing the secretion of apoB-containing lipoproteins. By contrast the mutation Tyr102Cys had no effect on apoB-48 secretion. Conclusions. This finding supports the notion that Thr26_27 delinsAsn is the cause of FHBL.

Published
2011

8. PREVALENCE OF ANGPTL3 AND APOB GENE MUTATIONS IN SUBJECTS WITH COMBINED HYPOLIPIDEMIA

Author

SPINA, Rossella, CEFALU', Angelo Baldassare, NOTO, Davide, VALENTI, Vincenza, FAYER, Francesca, DITTA, Mariangela, AVERNA, Maurizio, Pinotti E, Vigna G, Yue P, Schonfeld G, Kathiresan S, Tarugi P, Spina R, Cefalù AB, Noto D, Valenti V, Fayer, F, Pinotti E, Ditta M, Vigna G, Yue P, Schonfeld G, Kathiresan S, Tarugi P, and Averna M

Subjects
Settore MED/09 - Medicina Interna, ANGPTL3
Abstract

Introduction. Mutations of the ANGPTL3 gene have been found responsible for a novel form of primary hypobetalipoproteinemia (pHBL), the combined hypolipidemia, characterized by low total cholesterol (TC) and low HDL-cholesterol (HDL-C) levels. The aim of this work is to define the role of ANGPTL3 gene as determinant of the combined hypolipidemia phenotype in two large cohorts of 913 American and Italian subjects with primary hypobetalipoproteinemia (TC

Published
2011

12. A NOVEL LOSS OF FUNCTION MUTATION OF PCSK9 GENE

Author

Fasano, T, Bocchi, L, Di leo, E, Cefalù, B, Noto, D, Valenti, V, Guardamagna, Ornella, Calandra, S, Averna, M, Tarugi, P., FASANO T, BOCCHI L, DI LEO E, CEFALU' AB, NOTO D, VALENTI V, GUARDAMAGNA O, CALANDRA S, AVERNA MR, and TARUGI P

Subjects
LDLR gene, PCSK9 gene, loss of function, missense mutation, LDL-C, hypocholesterolemic effect
Published
2006

13. PREVALENCE OF APOB VARIANTS IN A SAMPLE OF SUBJECTS WITH HYPOCHOLESTEROLEMIA

Author

CEFALU', Angelo Baldassare, POLLACCIA, Daniela, VIVONA, Nicoletta, VALENTI, Vincenza, BARRACO, Giacoma, ONORATO, Karoly, TOIA, Giuseppe, FAYER, Francesca, MINA', Mariangela, BARBAGALLO, Carlo Maria, NOTARBARTOLO, Alberto, AVERNA, Maurizio, SAORIN, L, NOTO, D, AGLIASTRO, R, TARUGI, P, CEFALU, AB, POLLACCIA, D, VIVONA, N, SAORIN, L, VALENTI, V, BARRACO, G, NOTO, D, ONORATO, K, TOIA, G, FAYER, F, MINA, M, BARBAGALLO, C, AGLIASTRO, R, NOTARBARTOLO, A, TARUGI, P, and AVERNA, MR

Published
2005

19. European Lipoprotein Club: Report of the 24th ELC Annual Conference, Tutzing, 10-13 September 2001

Author

Dallinga-Thie, G., Bowyer, D., Dieplinger, H., Funke, H., Hofker, M., Jauhiainen, M., Nimpf, J., Staels, B., Talmud, P., Tarugi, P., Vascular Medicine, Experimental Vascular Medicine, Moleculaire Genetica, RS: NUTRIM School of Nutrition and Translational Research in Metabolism, and RS: CARIM School for Cardiovascular Diseases

Subjects
Political science, Immunology, Library science, Club, Cardiology and Cardiovascular Medicine
Published
2002

28. Plasma post-heparin lipolytic activity in rats with nephrotic syndrome

Author

Calandra S, Gottardi E, and Tarugi P

Subjects
Male, medicine.medical_specialty, Nephrotic Syndrome, business.industry, Heparin, Endocrinology, Diabetes and Metabolism, Lipolysis, Biochemistry (medical), Clinical Biochemistry, Rats, Inbred Strains, General Medicine, Lipoproteins, VLDL, Post-heparin lipolytic activity, medicine.disease, Biochemistry, Rats, Endocrinology, Internal medicine, Chylomicrons, Medicine, Animals, business, Nephrotic syndrome
Published
1983

29. Familial heterozygous hypobetalipoproteinemia, extrahepatic primary malignancy, and hepatocellular carcinoma

Author

Amedeo Lonardo, Tarugi, P., Ballarini, G., and Bagni, A.

Subjects
Male, Heterozygote, hypocholesterolemia, Carcinoma, Hepatocellular, Biopsy, Liver Neoplasms, Tonsillar Neoplasms, hypobetalipoproteinemia, Neoplasms, Second Primary, noncirrhotic liver, hepatocellular carcinoma, Hypobetalipoproteinemias, Liver, Lymphatic Metastasis, Humans, truncated apolipoprotein B, Extrahepatic primary milignancy, Aged, Apolipoproteins B

32. Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features

Author

Maurizio Averna, Gabriella Iannuzzo, Andrea Bartuli, Carlo Ripoli, Stefano Bertolini, Sebastiano Calandra, Patrizia Suppressa, Francesco Sbrana, Anastasia Ibba, Chiara Trenti, Alberico L. Catapano, Tommaso Fasano, Manuela Casula, Livia Pisciotta, Angelo B. Cefalù, Patrizia Tarugi, Tiziana Sampietro, Paolo Calabrò, Andrea Pasta, Paola Sabrina Buonuomo, Fulvio Sileo, M. G. Zenti, Chiara Pavanello, Sergio D'Addato, Marco Bucci, Marcello Arca, Arrigo F G Cicero, Emanuele A. Negri, Claudio Rabacchi, Laura D'Erasmo, Bertolini S., Calandra S., Arca M., Averna M., Catapano A.L., Tarugi P., Bartuli A., Bucci M., Buonuomo P.S., Calabro P., Casula M., Cefalu A.B., Cicero A., D'Addato S., D'Erasmo L., Fasano T., Iannuzzo G., Ibba A., Negri E.A., Pasta A., Pavanello C., Pisciotta L., Rabacchi C., Ripoli C., Sampietro T., Sbrana F., Sileo F., Suppressa P., Trenti C., Zenti M.G., Bertolini, S., Calandra, S., Arca, M., Averna, M., Catapano, A. L., Tarugi, P., Bartuli, A., Bucci, M., Buonuomo, P. S., Calabro', P., Casula, M., Cefalu, A. B., Cicero, A., D'Addato, S., D'Erasmo, L., Fasano, T., Iannuzzo, G., Ibba, A., Negri, E. A., Pasta, A., Pavanello, C., Pisciotta, L., Rabacchi, C., Ripoli, C., Sampietro, T., Sbrana, F., Sileo, F., Suppressa, P., Trenti, C., Zenti, M. G., Bertolini, S, Calandra, S, Arca, M, Averna, M, Catapano, Al, Tarugi, P, IAndrea Bartuli, 7, Marco, Bucci, Paola Sabrina Buonuomo, Calabro', Paolo, Manuela, Casula, Angelo Baldassare Cefalù, Arrigo, Cicero, Sergio, D'Addato, Laura, D'Erasmo, Tommaso, Fasano, Iannuzzo, Gabriella, Anastasia, Ibba, Emanuele, A Negri Andrea Pasta, Chiara, Pavanello, Livia, Pisciotta, Claudio, Rabacchi, Carlo, Ripoli, Tiziana, Sampietro, Francesco, Sbrana, Fulvio, Sileo, Patrizia, Suppressa, Chiara, Trenti, and Maria Grazia Zenti

Subjects
Adult, 0301 basic medicine, medicine.medical_specialty, Candidate gene, Genotype-phenotype correlation, Apolipoprotein B, Candidate genes, Genotype-phenotype correlations, Homozygous familial hypercholesterolemia, Pathogenic variants, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Compound heterozygosity, Hyperlipoproteinemia Type II, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, biology, business.industry, PCSK9, Homozygote, Genetic disorder, medicine.disease, Phenotype, 030104 developmental biology, Endocrinology, Italy, Receptors, LDL, Autosomal Recessive Hypercholesterolemia, Mutation, LDL receptor, biology.protein, lipids (amino acids, peptides, and proteins), Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, business
Abstract

Background and aims Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely elevated plasma levels of low density lipoprotein cholesterol (LDL-C) and high risk of premature atherosclerotic cardiovascular disease (ASCVD). HoFH is caused by pathogenic variants in several genes, such as LDLR, APOB and PCSK9, responsible for autosomal dominant hypercholesterolemia (ADH), and LDLRAP1 responsible for autosomal recessive hypercholesterolemia (ARH). Aim of this study was the review of the clinical and molecular features of patients with HoFH identified in Italy from 1989 to 2019. Methods Data were collected from lipid clinics and laboratories, which had performed molecular diagnosis in suspected HoFH. Clinical data included baseline lipid levels and ASCVD events. Results A total of 125 subjects with ADH were identified, of whom 60 were true homozygotes, 58 compound heterozygotes and 7 double heterozygotes for LDLR (likely) pathogenic variants. Compared with compound heterozygotes, true homozygotes showed a more severe lipid phenotype and more ASCVD events. ADH carriers of LDLR negative variants (R-NEG) presented with a more aggressive phenotype, as compared to carriers of LDLR defective variants (R-DEF). Kaplan-Meier analysis showed that the median age of ASCVD event-free survival was 25 years of age in R-NEG as opposed to 50 years of age in R-DEF patients. A total of 66 patients with ARH were also identified, of whom 46 were homozygotes and 20 compound heterozygotes. The phenotypic features of ARH patients were similar to those of R-DEF/ADH patients. Overall, 45% ADH patients and 33% ARH patients did not meet the classic diagnostic criteria for HoFH. Conclusions In our cohort, the phenotypic variability of HoFH was dependent on the candidate gene involved and the functional impact of its variants on the LDL receptor pathway.

Published
2020

33. Molecular diagnosis of hypobetalipoproteinemia: an ENID review

Author

Patrizia Tarugi, Angelo B. Cefalù, Sebastiano Calandra, Stefano Bertolini, Enza Di Leo, Maurizio Averna, Davide Noto, Lucia Magnolo, Luigi Cattin, TARUGI, P, AVERNA, M, DI LEO, E, CEFALU, AB, NOTO, D, MAGNOLO, L, CATTIN, L, BERTOLINI, S, CALANDRA, S, Tarugi, P., Averna, M., Di Leo, E., Cefalù, A. B., Noto, D., Magnolo, L., Cattin, Luigi, Bertolini, S., and Calandra, S.

Subjects
Male, Candidate gene, Settore MED/09 - Medicina Interna, Apolipoprotein B, Genotype, Locus (genetics), Biology, Polymorphism, Single Nucleotide, PCSK9 Gene, medicine, Humans, Familial hypobetalipoproteinemia, Genetic Testing, APOB gene, Apolipoproteins B, Genetics, PCSK9, Abetalipoproteinemia, Chylomicron retention disease, medicine.disease, European Network for Inherited Dyslipidemia (ENID), Phenotype, PCSK9 gene, Hypobetalipoproteinemia, Familial, Apolipoprotein B, Mutation, biology.protein, lipids (amino acids, peptides, and proteins), Female, Hypobetalipoproteinemia, MTP gene, Cardiology and Cardiovascular Medicine, Carrier Proteins, uropean Network for Inherited Dyslipidemia (ENID), European Network for Inherited Dyslipidemia (ENID), Familial hypobetalipoproteinemia, Abetalipoproteinemia, Chylomicron retention disease
Abstract

Primary hypobetalipoproteinemia (HBL) includes a group of genetic disorders: abetalipoproteinemia (ABL) and chylomicron retention disease (CRD), with a recessive transmission, and familial hypobetalipoproteinemia (FHBL) with a co-dominant transmission. ABL and CRD are rare disorders due to mutations in the MTP and SARA2 genes, respectively. Heterozygous FHBL is much more frequent. FHBL subjects often have fatty liver and, less frequently, intestinal fat malabsorption. FHBL may be linked or not to the APOB gene. Most mutations in APOB gene cause the formation of truncated forms of apoB which may or may be not secreted into the plasma. Truncated apoBs with a size below that of apoB-30 are not detectable in plasma; they are more frequent in patients with the most severe phenotype. Only a single amino acid substitution (R463W) has been reported as the cause of FHBL. Approximately 50% of FHBL subjects are carriers of pathogenic mutations in APOB gene; therefore, a large proportion of FHBL subjects have no apoB gene mutations or are carriers of rare amino acid substitutions in apoB with unknown effect. In some kindred FHBL is linked to a locus on chromosome 3 (3p21) but the candidate gene is unknown. Recently a FHBL plasma lipid phenotype was observed in carriers of mutations of the PCSK9 gene causing loss of function of the encoded protein, a proprotein convertase which regulates LDL-receptor number in the liver. Inactivation of this enzyme is associated with an increased LDL uptake and hypobetalipoproteinemia. HBL carriers of PCSK9 mutations do not develop fatty liver disease.

Published
2006

34. Worldwide experience of homozygous familial hypercholesterolaemia:retrospective cohort study

Author

Tycho R Tromp, Merel L Hartgers, G Kees Hovingh, Antonio J Vallejo-Vaz, Kausik K Ray, Handrean Soran, Tomas Freiberger, Stefano Bertolini, Mariko Harada-Shiba, Dirk J Blom, Frederick J Raal, Marina Cuchel, Tycho R. Tromp, Merel L. Hartgers, G. Kees Hovingh, Antonio J. Vallejo-Vaz, Kausik K. Ray, Stefano A. Bertolini, Jing Pang, Gerald F. Watts, Susanne Greber-Platzer, Martin Mäser, Thomas M. Stulnig, Christoph F. Ebenbichler, Khalid Bin Thani, David Cassiman, Olivier S. Descamps, Daisy Rymen, Peter Witters, Raul D. Santos, Liam R. Brunham, Gordon A. Francis, Jacques Genest, Robert A. Hegele, Brooke A. Kennedy, Isabelle Ruel, Mark H. Sherman, Long Jiang, Luya Wang, Željko Reiner, Vladimir Blaha, Richard Ceska, Jana Dvorakova, Lubomir Dlouhy, Pavel Horak, Vladimir Soska, Lukas Tichy, Robin Urbanek, Helena Vaverkova, Michal Vrablik, Stanislav Zemek, Lukas Zlatohlavek, Sameh Emil, Tarek Naguib, Ashraf Reda, Sophie Béliard, Eric Bruckert, Antonio Gallo, Moses S. Elisaf, Genovefa Kolovou, Hofit Cohen, Ronen Durst, Eldad J. Dann, Avishay Elis, Osama Hussein, Eran Leitersdorf, Daniel Schurr, Nitika Setia, Ishwar C. Verma, Mohammed D. Alareedh, Mutaz Al-Khnifsawi, Ali F. Abdalsahib Al-Zamili, Sabah H. Rhadi, Foaad K. Shaghee, Marcello Arca, Maurizio Averna, Andrea Bartuli, Marco Bucci, Paola S. Buonuomo, Paolo Calabrò, Sebastiano Calandra, Manuela Casula, Alberico L. Catapano, Angelo B. Cefalù, Arrigo F.G. Cicero, Sergio D'Addato, Laura D'Erasmo, Alessia Di Costanzo, Tommaso Fasano, Marta Gazzotti, Antonina Giammanco, Gabriella Iannuzzo, Anastasia Ibba, Emanuele A. Negri, Andrea Pasta, Chiara Pavanello, Livia Pisciotta, Claudio Rabacchi, Carlo Ripoli, Tiziana Sampietro, Francesco Sbrana, Fulvio Sileo, Patrizia Suppressa, Patrizia Tarugi, Chiara Trenti, Maria G. Zenti, Mika Hori, Mahmoud H. Ayesh, Sami T. Azar, Fadi F. Bitar, Akl C. Fahed, Elie M. Moubarak, Georges Nemer, Hapizah M. Nawawi, Ramón Madriz, Roopa Mehta, Arjen J. Cupido, Joep C. Defesche, M. Doortje Reijman, Jeanine E. Roeters-van Lennep, Erik S.G. Stroes, Albert Wiegman, Linda Zuurbier, Khalid Al-Waili, Fouzia Sadiq, Krzysztof Chlebus, Mafalda Bourbon, Isabel M. Gaspar, Katarina S. Lalic, Marat V. Ezhov, Andrey V. Susekov, Urh Groselj, Min-Ji Charng, Weerapan Khovidhunkit, Melih Aktan, Bulent B. Altunkeser, Sinan Demircioglu, Melis Kose, Cumali Gokce, Osman Ilhan, Meral Kayikcioglu, Leyla G. Kaynar, Irfan Kuku, Erdal Kurtoglu, Harika Okutan, Osman I. Ozcebe, Zafer Pekkolay, Saim Sag, Osman Z. Salcioglu, Ahmet Temizhan, Mustafa Yenercag, Mehmet Yilmaz, Hamiyet Yilmaz Yasar, Olena Mitchenko, Alexander R.M. Lyons, Christophe A.T. Stevens, Julie A. Brothers, Lisa C. Hudgins, Christina Nguyen, Rano Alieva, Aleksandr Shek, Doan-Loi Do, Ngoc-Thanh Kim, Hong-An Le, Thanh-Tung Le, Mai-Ngoc T. Nguyen, Thanh-Huong Truong, Dirk J. Blom, Frederick J. Raal, VU University medical center, Tromp T.R., Hartgers M.L., Hovingh G.K., Vallejo-Vaz A.J., Ray K.K., Soran H., Freiberger T., Bertolini S., Harada-Shiba M., Blom D.J., Raal F.J., Cuchel M., Bertolini S.A., Pang J., Watts G.F., Greber-Platzer S., Maser M., Stulnig T.M., Ebenbichler C.F., Bin Thani K., Cassiman D., Descamps O.S., Rymen D., Witters P., Santos R.D., Brunham L.R., Francis G.A., Genest J., Hegele R.A., Kennedy B.A., Ruel I., Sherman M.H., Jiang L., Wang L., Reiner Z., Blaha V., Ceska R., Dvorakova J., Dlouhy L., Horak P., Soska V., Tichy L., Urbanek R., Vaverkova H., Vrablik M., Zemek S., Zlatohlavek L., Emil S., Naguib T., Reda A., Beliard S., Bruckert E., Gallo A., Elisaf M.S., Kolovou G., Cohen H., Durst R., Dann E.J., Elis A., Hussein O., Leitersdorf E., Schurr D., Setia N., Verma I.C., Alareedh M.D., Al-Khnifsawi M., Abdalsahib Al-Zamili A.F., Rhadi S.H., Shaghee F.K., Arca M., Averna M., Bartuli A., Bucci M., Buonuomo P.S., Calabro P., Calandra S., Casula M., Catapano A.L., Cefalu A.B., Cicero A.F.G., D'Addato S., D'Erasmo L., Di Costanzo A., Fasano T., Gazzotti M., Giammanco A., Iannuzzo G., Ibba A., Negri E.A., Pasta A., Pavanello C., Pisciotta L., Rabacchi C., Ripoli C., Sampietro T., Sbrana F., Sileo F., Suppressa P., Tarugi P., Trenti C., Zenti M.G., Hori M., Ayesh M.H., Azar S.T., Bitar F.F., Fahed A.C., Moubarak E.M., Nemer G., Nawawi H.M., Madriz R., Mehta R., Cupido A.J., Defesche J.C., Reijman M.D., Roeters-van Lennep J.E., Stroes E.S.G., Wiegman A., Zuurbier L., Al-Waili K., Sadiq F., Chlebus K., Bourbon M., Gaspar I.M., Lalic K.S., Ezhov M.V., Susekov A.V., Groselj U., Charng M.-J., Khovidhunkit W., Aktan M., Altunkeser B.B., Demircioglu S., Kose M., Gokce C., Ilhan O., Kayikcioglu M., Kaynar L.G., Kuku I., Kurtoglu E., Okutan H., Ozcebe O.I., Pekkolay Z., Sag S., Salcioglu O.Z., Temizhan A., Yenercag M., Yilmaz M., Yilmaz Yasar H., Mitchenko O., Lyons A.R.M., Stevens C.A.T., Brothers J.A., Hudgins L.C., Nguyen C., Alieva R., Shek A., Do D.-L., Kim N.-T., Le H.-A., Le T.-T., Nguyen M.-N.T., Truong T.-H., University of Amsterdam, University of Pennsylvania, European Atherosclerosis Society, Experimental Vascular Medicine, Graduate School, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, Human Genetics, Paediatric Metabolic Diseases, ACS - Diabetes & metabolism, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ACS - Heart failure & arrhythmias, R Tromp, Tycho, L Hartgers, Merel, Kees Hovingh, G, J Vallejo-Vaz, Antonio, K Ray, Kausik, Soran, Handrean, Freiberger, Toma, A Bertolini, Stefano, Harada-Shiba, Mariko, Pang, Jing, F Watts, Gerald, Greber-Platzer, Susanne, Mäser, Martin, M Stulnig, Thoma, F Ebenbichler, Christoph, Bin Thani, Khalid, Cassiman, David, S Descamps, Olivier, Rymen, Daisy, Witters, Peter, D Santos, Raul, R Brunham, Liam, A Francis, Gordon, Genest, Jacque, A Hegele, Robert, A Kennedy, Brooke, Ruel, Isabelle, H Sherman, Mark, Jiang, Long, Wang, Luya, Reiner, Željko, Blaha, Vladimir, Ceska, Richard, Dvorakova, Jana, Dlouhy, Lubomir, Horak, Pavel, Soska, Vladimir, Tichy, Luka, Urbanek, Robin, Vaverkova, Helena, Vrablik, Michal, Zemek, Stanislav, Zlatohlavek, Luka, Emil, Sameh, Naguib, Tarek, Reda, Ashraf, Béliard, Sophie, Bruckert, Eric, Gallo, Antonio, S Elisaf, Mose, Kolovou, Genovefa, Cohen, Hofit, Durst, Ronen, J Dann, Eldad, Elis, Avishay, Hussein, Osama, Leitersdorf, Eran, Schurr, Daniel, Setia, Nitika, C Verma, Ishwar, D Alareedh, Mohammed, Al-Khnifsawi, Mutaz, F Abdalsahib Al-Zamili, Ali, H Rhadi, Sabah, K Shaghee, Foaad, Arca, Marcello, Averna, Maurizio, Bartuli, Andrea, Bucci, Marco, S Buonuomo, Paola, Calabrò, Paolo, Calandra, Sebastiano, Casula, Manuela, L Catapano, Alberico, B Cefalù, Angelo, G Cicero, Arrigo F, D'Addato, Sergio, D'Erasmo, Laura, Di Costanzo, Alessia, Fasano, Tommaso, Gazzotti, Marta, Giammanco, Antonina, Iannuzzo, Gabriella, Ibba, Anastasia, A Negri, Emanuele, Pasta, Andrea, Pavanello, Chiara, Pisciotta, Livia, Rabacchi, Claudio, Ripoli, Carlo, Sampietro, Tiziana, Sbrana, Francesco, Sileo, Fulvio, Suppressa, Patrizia, Tarugi, Patrizia, Trenti, Chiara, G Zenti, Maria, Hori, Mika, H Ayesh, Mahmoud, T Azar, Sami, F Bitar, Fadi, C Fahed, Akl, M Moubarak, Elie, Nemer, George, M Nawawi, Hapizah, Madriz, Ramón, Mehta, Roopa, J Cupido, Arjen, C Defesche, Joep, Doortje Reijman, M, E Roeters-van Lennep, Jeanine, G Stroes, Erik S, Wiegman, Albert, Zuurbier, Linda, Al-Waili, Khalid, Sadiq, Fouzia, Chlebus, Krzysztof, Bourbon, Mafalda, M Gaspar, Isabel, S Lalic, Katarina, V Ezhov, Marat, V Susekov, Andrey, Groselj, Urh, Charng, Min-Ji, Khovidhunkit, Weerapan, Aktan, Melih, B Altunkeser, Bulent, Demircioglu, Sinan, Kose, Meli, Gokce, Cumali, Ilhan, Osman, Kayikcioglu, Meral, G Kaynar, Leyla, Kuku, Irfan, Kurtoglu, Erdal, Okutan, Harika, I Ozcebe, Osman, Pekkolay, Zafer, Sag, Saim, Z Salcioglu, Osman, Temizhan, Ahmet, Yenercag, Mustafa, Yilmaz, Mehmet, Yilmaz Yasar, Hamiyet, Mitchenko, Olena, M Lyons, Alexander R, T Stevens, Christophe A, A Brothers, Julie, C Hudgins, Lisa, Nguyen, Christina, Alieva, Rano, Shek, Aleksandr, Do, Doan-Loi, Kim, Ngoc-Thanh, Le, Hong-An, Le, Thanh-Tung, T Nguyen, Mai-Ngoc, Truong, Thanh-Huong, J Blom, Dirk, J Raal, Frederick, and Cuchel, Marina

Subjects
Adult, Male, Homozygous Familial Hypercholesterolemia, Adolescent, retrospective study, CHILDREN, Doenças Cardio e Cérebro-vasculares, Cohort Studies, Young Adult, Medicine, General & Internal, General & Internal Medicine, Cardiovascular Disease, Humans, Registries, LIPOPROTEIN-APHERESIS, Child, 11 Medical and Health Sciences, Retrospective Studies, Homozygous Familial Hypercholesterolaemia International Clinical Collaborators, Science & Technology, GUIDANCE, clinical characteristic, EVOLOCUMAB, Homozygous familial hypercholesterolemia, Worldwide, Therapies, Cardiovascular disease, General Medicine, CARE, OPEN-LABEL, EFFICACY, INSIGHTS, Child, Preschool, outcome, Female, genetic, Familial Hypercholesterolaemia, Life Sciences & Biomedicine
Abstract

[Background]: Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally., [Methods]: The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005., [Findings]: Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12∙0 years (IQR 5∙5–27∙0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14∙7 mmol/L (IQR 11∙6–18∙4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3∙93 mmol/L, IQR 2∙6–5∙8) versus non-highincome countries (9∙3 mmol/L, 6∙7–12∙7), with greater use of three or more lipid-lowering therapies (LLT; highincome 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24∙5 years (IQR 17∙0–34∙5) versus 37∙0 years (29∙0–49∙0) in high-income countries (adjusted hazard ratio 1∙64, 95% CI 1∙13–2∙38)., [Interpretation]: Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH., Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; and European Atherosclerosis Society

Published
2022

35. In vitro functional characterization of splicing variants of the APOB gene found in familial hypobetalipoproteinemia

Author

Enza Di Leo, Davide Bocchi, Patrizia Tarugi, Stefano Bertolini, Maria Luisa Simone, Claudio Rabacchi, Antonello Pietrangelo, Livia Pisciotta, Sebastiano Calandra, Sergio D'Addato, Rabacchi C., Simone M.L., Pisciotta L., Di Leo E., Bocchi D., Pietrangelo A., D'Addato S., Bertolini S., Calandra S., and Tarugi P.

Subjects
Adult, Male, Nonsynonymous substitution, Truncated apoB, Apolipoprotein B, Splicing variants, RNA Splicing, Endocrinology, Diabetes and Metabolism, In silico, Intron, 030204 cardiovascular system & hematology, Chlorocebus aethiop, Splicing variant, Hypobetalipoproteinemias, 03 medical and health sciences, Exon, 0302 clinical medicine, COS Cell, Chlorocebus aethiops, Internal Medicine, Animals, Humans, Medicine, 030212 general & internal medicine, Familial hypobetalipoproteinemia, APOB gene, Aged, Genetics, Nutrition and Dietetics, biology, Animal, business.industry, Middle Aged, Introns, Exon skipping, Truncated apoBs, COS Cells, Apolipoprotein B-100, RNA splicing, Codon, Terminator, biology.protein, Female, Cardiology and Cardiovascular Medicine, business, Hypobetalipoproteinemia, Human, Minigene
Abstract

Background: Familial hypobetalipoproteinemia type 1 (FHBL-1) is a codominant disorder characterized by greatly reduced plasma levels of total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B. Rare exonic pathogenic variants of APOB gene (nonsense variants, minute deletions/insertions and nonsynonymous variants) have been frequently reported in subjects with FHBL-1. Also, rare intronic variants of APOB located at intron/exon junctions and assumed to affect splicing have been reported. However, the pathogenicity of most of these intronic variants remains to be established. Objective: The objective of this study was the in vitro functional characterization of six splicing variants of APOB gene identified in seven putative FHBL-1 heterozygotes. Methods: ApoB minigenes harboring each variant were expressed in COS-1 cells and their transcripts were sequenced. Results: Four novel variants (c.237+1G>A, c.818+5G>A, c.3000-1G>T, and c.3842+1G>A), predicted in silico to obliterate splice site activity, were found to generate abnormal transcripts. The abnormal transcripts were generated by the activation of cryptic splice sites or exon skipping. All these transcripts harbored a premature termination codon and were predicted to encode truncated apoBs devoid of function. The predicted translation products were: i) p.(Lys41Serfs*2) and p.(Val80Ilefs*10) for c.237+1G>A; ii) p.(Asn274*) for c.818+5G>A; iii) p.(Leu1001Alafs*10) for c.3000-1G>T, and iv) p.(Ser1281Argfs*2) for c.3842+1G>A. Two previously annotated rare variants (c.905-15C>G and c.1618-4G>A) with uncertain effect in silico were found to generate only wild-type transcripts. Conclusions: These in vitro minigene expression studies support the assignment of pathogenicity to four novel splice site variants of APOB gene found in FHBL-1.

Published
2019

36. Le basi cellulari e molecolari delle malattie per le lauree triennali e magistrali

Author

G. Accardi, E. Alesse, L. Altucci, S. Ando', A. Arcaro, S. Baldovino, G. Berton, D. Bonofiglio, C. Caruso, G. Castoria, S. Catalano, G. P. Cetrangolo, M. Corsi Romanelli, E. Di Zazzo, A. Dobrina, E. Dozio, S. Dusi, L. Formisano, S. Formisano, F. Gentile, M. Lanzino, E. Menegatti, A. Nebbioso, F. Olivieri, A. Pompella, D. Roccatello, S. Sciascia, D. Sisci, L. A. Stivala, F. P. Tamburo, P. Tarugi, E. Vecile, E. Vinello, G. Accardi, E. Alesse, L. Altucci, S. Ando', A. Arcaro, S. Baldovino, G. Berton, D. Bonofiglio, C. Caruso, G. Castoria, S. Catalano, G. P. Cetrangolo, M. Corsi Romanelli, E. Di Zazzo, A. Dobrina, E. Dozio, S. Dusi, L. Formisano, S. Formisano, F. Gentile, M. Lanzino, E. Menegatti, A. Nebbioso, F. Olivieri, A. Pompella, D. Roccatello, S. Sciascia, D. Sisci, L. A. Stivala, F.P. Tamburo, P. Tarugi, E. Vecile, E. Vinello, Albi - Ambesi Impionbato - Curcio - Moncharmont - Palese, Accardi, G., Alesse, E., Altucci, L., Ando', S., Arcaro, A., Baldovino, S., Berton, G., Bonofiglio, D., Caruso, C., Castoria, G., Catalano, S., Cetrangolo, G. P., Corsi Romanelli, M., Di Zazzo, E., Dobrina, A., Dozio, E., Dusi, S., Formisano, L., Formisano, S., Gentile, F., Lanzino, M., Menegatti, E., Nebbioso, A., Olivieri, F., Pompella, A., Roccatello, D., Sciascia, S., Sisci, D., Stivala, L. A., Tamburo, F. P., Tarugi, P., Vecile, E., and Vinello, E.

Published
2018

37. Threshold Effects of Circulating Angiopoietin-Like 3 Levels on Plasma Lipoproteins

Author

Maurizio Averna, Sotirios Tsimikas, Patrizia Tarugi, Marcello Arca, Michael D. Shapiro, Jessica Minnier, Hagai Tavori, Sergio Fazio, Fazio, S., Minnier, J., Shapiro, M., Tsimikas, S., Tarugi, P., Averna, M., Arca, M., and Tavori, H.

Subjects
0301 basic medicine, Male, Apolipoprotein B, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Biochemistry, Lipoprotein particle, PCSK9, Cohort Studies, Hypobetalipoproteinemias, chemistry.chemical_compound, Endocrinology, ANGPTL3, biology, Chemistry, Middle Aged, Pedigree, Lipoproteins, LDL, Phenotype, Kexin, lipids (amino acids, peptides, and proteins), Female, familial combined hypolipidemia, Lipoproteins, HDL, Adult, medicine.medical_specialty, Heterozygote, Blotting, Western, 03 medical and health sciences, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Clinical Research Articles, Aged, Angiopoietin-Like Protein 3, Apolipoproteins B, Cholesterol, Biochemistry (medical), medicine.disease, 030104 developmental biology, Angiopoietin-like Proteins, LDL receptor, Multivariate Analysis, Mutation, biology.protein, Linear Models, familial combined hypobetalipoproteinemia, Hypobetalipoproteinemia, Angiopoietins, Lipoprotein
Abstract

Context Angiopoietin-like 3 (ANGPTL3) deficiency in plasma due to loss-of-function gene mutations results in familial combined hypobetalipoproteinemia type 2 (FHBL2) in homozygotes. However, the lipid phenotype in heterozygotes is much milder and does not appear to relate directly to ANGPTL3 levels. Furthermore, the low-density lipoprotein (LDL) phenotype in carriers of ANGPTL3 mutations is unexplained. Objective To determine whether reduction below a critical threshold in plasma ANGPTL3 levels is a determinant of lipoprotein metabolism in FHBL2, and to determine whether proprotein convertase subtilisin kexin type 9 (PCSK9) is involved in determining low LDL levels in this condition. Design We studied subjects from 19 families with ANGPTL3 mutations and subjects with familial combined hypobetalipoproteinemia type 1 (FHBL1) due to truncated apolipoprotein B (apoB) species. Results First, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and HDL and LDL particle concentration correlated with plasma ANGPTL3 levels but only when the latter was Conclusions Our results suggest that the hypolipidemic effects of ANGPTL3 mutations in FHBL2 are dependent on a threshold of plasma ANGPTL3 levels, with differential effects on various lipoprotein particles. The increased inactivation of PCSK9 by furin in FHBL1 and FHBL2 is likely to cause increased LDL clearance and suggests novel therapeutic avenues.

Published
2017

38. Familial hypercholesterolemia: The Italian Atherosclerosis Society Network (LIPIGEN)

Author

Averna, Maurizio, Cefalã¹, Angelo B., Casula, Manuela, Noto, Davide, Arca, Marcello, Bertolini, Stefano, Calandra, Sebastiano, Catapano, Alberico L., Tarugi, Patrizia, Catapano, Alberico Luigi, Pellegatta, Fabio, Angelico, Francesco, Bartuli, Andrea, Biasucci, Giacomo, Biolo, Gianni, Bonanni, Luca, Bonomo, Katia, Borghi, Claudio, Bossi, Antonio Carlo, Branchi, Adriana, Carubbi, Francesca, Cipollone, Francesco, Citroni, Nadia, Federici, Massimo, Ferri, Claudio, Fiorenza, Anna Maria, Giaccari, Andrea, Giorgino, Francesco, Guardamagna, Ornella, Iannuzzi, Arcangelo, Iughetti, Lorenzo, Lupattelli, Graziana, Mandraffino, Giuseppe, Marcucci, Rossella, Mombelli, Giuliana, Muntoni, Sandro, Pecchioli, Valerio, Pederiva, Cristina, Pipolo, Antonio, Pisciotta, Livia, Pujia, Arturo, Purrello, Francesco, Repetti, Elena, Rubba, Paolo, SabbÃ&nbsp, Carlo, Sampietro, Tiziana, Sarzani, Riccardo, Tagliabue, Milena Paola, Trenti, Chiara, Vigna, Giovanni Battista, Werba, Josà Pablo, Zambon, Sabina, Zenti, Maria Grazia, Montali, Anna, Fortunato, Giuliana, Grigore, Liliana, Del Ben, Maria, Maranghi, Marianna, Barbagallo, Carlo M., Buonuomo, Paola Sabrina, Capra, Maria Elena, Vinci, Pierandrea, D'Addato, Sergio, Galbiati, Stella, Nascimbeni, Fabio, Bucci, Marco, Spagnoli, Walter, Cardolini, Iris, Cervelli, Nazzareno, Emanuela, Colombo, Vinsin, A. Sun, Laviola, Luigi, Bello, Francesca, Chiariello, Giuseppe, Predieri, Barbara, Siepi, Donatella, Saitta, Antonino, Giusti, Betti, Pavanello, Chiara, Lussu, Milena, Prati, Lucia, Banderali, Giuseppe, Balleari, Giulia, Montalcini, Tiziana, Scicali, Roberto, Gentile, Luigi, Gentile, Marco, Suppressa, Patrizia, Sbrana, Francesco, Cocci, Guido, Benso, Andrea, Negri, Emanuele Alberto, Ghirardello, Omar, Lorenzo, Vigo, Zambon, Alberto, Enzo, Bonora, Minicocci, Ilenia, Spina, Rossella, Orlando, Camilla, Di Taranto, Maria Donata, Chiodo, Lorenzo, Garlaschelli, Katia, Manzato, Enzo, Tragni, Elena, Averna, M., Cefalu', A., Casula, M., Noto, D., Arca, M., Bertolini, S., Calandra, S., Catapano, A., Tarugi, P., Pellegatta, F., Angelico, F., Bartuli, A., Biasucci, G., Biolo, G., Bonanni, L., Bonomo, K., Borghi, C., Bossi, A., Branchi, A., Carubbi, F., Cipollone, F., Citroni, N., Federici, M., Ferri, C., Fiorenza, A., Giaccari, A., Giorgino, F., Guardamagna, O., Iannuzzi, A., Iughetti, L., Lupattelli, G., Mandraffino, G., Marcucci, R., Mombelli, G., Muntoni, S., Pecchioli, V., Pederiva, C., Pipolo, A., Pisciotta, L., Pujia, A., Purrello, F., Repetti, E., Rubba, P., Sabbã , C., Sampietro, T., Sarzani, R., Tagliabue, M., Trenti, C., Vigna, G., Werba, J., Zambon, S., Zenti, M., Montali, A., Fortunato, G., Grigore, L., Del Ben, M., Maranghi, M., Cefalã¹, A., Barbagallo, C., Buonuomo, P., Capra, M., Vinci, P., D'Addato, S., Galbiati, S., Nascimbeni, F., Bucci, M., Spagnoli, W., Cardolini, I., Cervelli, N., Emanuela, C., Vinsin, A., Laviola, L., Bello, F., Chiariello, G., Predieri, B., Siepi, D., Saitta, A., Giusti, B., Pavanello, C., Lussu, M., Prati, L., Banderali, G., Balleari, G., Montalcini, T., Scicali, R., Gentile, L., Gentile, M., Suppressa, P., Sbrana, F., Cocci, G., Benso, A., Negri, E., Ghirardello, O., Lorenzo, V., Zambon, A., Enzo, B., Minicocci, I., Spina, R., Orlando, C., Di Taranto, M., Chiodo, L., Garlaschelli, K., Manzato, E., Tragni, E., Averna, Maurizio, Cefalã¹, Angelo B., Casula, Manuela, Noto, Davide, Arca, Marcello, Bertolini, Stefano, Calandra, Sebastiano, Catapano, Alberico L., Tarugi, Patrizia, Catapano, Alberico Luigi, Pellegatta, Fabio, Angelico, Francesco, Bartuli, Andrea, Biasucci, Giacomo, Biolo, Gianni, Bonanni, Luca, Bonomo, Katia, Borghi, Claudio, Bossi, Antonio Carlo, Branchi, Adriana, Carubbi, Francesca, Cipollone, Francesco, Citroni, Nadia, Federici, Massimo, Ferri, Claudio, Fiorenza, Anna Maria, Giaccari, Andrea, Giorgino, Francesco, Guardamagna, Ornella, Iannuzzi, Arcangelo, Iughetti, Lorenzo, Lupattelli, Graziana, Mandraffino, Giuseppe, Marcucci, Rossella, Mombelli, Giuliana, Muntoni, Sandro, Pecchioli, Valerio, Pederiva, Cristina, Pipolo, Antonio, Pisciotta, Livia, Pujia, Arturo, Purrello, Francesco, Repetti, Elena, Rubba, Paolo, Sabbã , Carlo, Sampietro, Tiziana, Sarzani, Riccardo, Tagliabue, Milena Paola, Trenti, Chiara, Vigna, Giovanni Battista, Werba, Josã Pablo, Zambon, Sabina, Zenti, Maria Grazia, Montali, Anna, Fortunato, Giuliana, Grigore, Liliana, DEL BELLO, Francesca, Maranghi, Marianna, Barbagallo, Carlo M., Buonuomo, Paola Sabrina, Capra, Maria Elena, Vinci, Pierandrea, D'Addato, Sergio, Galbiati, Stella, Nascimbeni, Fabio, Bucci, Marco, Spagnoli, Walter, Cardolini, Iri, Cervelli, Nazzareno, Emanuela, Colombo, Vinsin, A. Sun, Laviola, Luigi, Bello, Francesca, Chiariello, Giuseppe, Predieri, Barbara, Siepi, Donatella, Saitta, Antonino, Giusti, Betti, Pavanello, Chiara, Lussu, Milena, Prati, Lucia, Banderali, Giuseppe, Balleari, Giulia, Montalcini, Tiziana, Scicali, Roberto, Gentile, Luigi, Gentile, Marco, Suppressa, Patrizia, Sbrana, Francesco, Cocci, Guido, Benso, Andrea, Negri, Emanuele Alberto, Ghirardello, Omar, Lorenzo, Vigo, Zambon, Alberto, Enzo, Bonora, Minicocci, Ilenia, Spina, Rossella, Orlando, Camilla, Di Taranto, Maria Donata, Chiodo, Lorenzo, Garlaschelli, Katia, Manzato, Enzo, Tragni, Elena, Cefalù, Angelo B., Sabbà, Carlo, Werba, Josè Pablo, Del Ben, Maria, and Colombo, Emanuela

Subjects
0301 basic medicine, Candidate gene, Genetic testing, Settore MED/09 - Medicina Interna, Databases, Factual, DNA Mutational Analysis, Disease, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, 0302 clinical medicine, Dyslipidemias, National network, Internal Medicine, Cardiology and Cardiovascular Medicine, Risk Factors, Prospective Studies, Program Development, Prospective cohort study, medicine.diagnostic_test, General Medicine, Prognosis, Cholesterol, Phenotype, Italy, Genetic Markers, medicine.medical_specialty, MEDLINE, Hyperlipoproteinemia Type II, 03 medical and health sciences, Databases, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Factual, Retrospective Studies, business.industry, Settore MED/13 - ENDOCRINOLOGIA, Retrospective cohort study, medicine.disease, Atherosclerosis, Mutation, 030104 developmental biology, Endocrinology, Dyslipidemia, Genetic marker, business
Abstract

Background and aims: Primary dyslipidemias are a heterogeneous group of disorders characterized by abnormal levels of circulating lipoproteins. Among them, familial hypercholesterolemia is the most common lipid disorder that predisposes for premature cardiovascular disease. We set up an Italian nationwide network aimed at facilitating the clinical and genetic diagnosis of genetic dyslipidemias named LIPIGEN (LIpid TransPort Disorders Italian GEnetic Network). Methods: Observational, multicenter, retrospective and prospective study involving about 40 Italian clinical centers. Genetic testing of the appropriate candidate genes at one of six molecular diagnostic laboratories serving as nationwide DNA diagnostic centers. Results and conclusions: From 2012 to October 2016, available biochemical and clinical information of 3480 subjects with familial hypercholesterolemia identified according to the Dutch Lipid Clinic Network (DLCN) score were included in the database and genetic analysis was performed in 97.8% of subjects, with a mutation detection rate of 92.0% in patients with DLCN score >= 6. The establishment of the LIPIGEN network will have important effects on clinical management and it will improve the overall identification and treatment of primary dyslipidemias in Italy. (C) 2017 The Authors. Published by Elsevier Ireland Ltd.

Published
2017

39. Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study

Author

Pirillo, Angela, Garlaschelli, Katia, Arca, Marcello, Averna, Maurizio, Bertolini, Stefano, Calandra, Sebastiano, Tarugi, Patrizia, Catapano, Alberico L., Catapano, Alberico Luigi, Pellegatta, Fabio, Angelico, Francesco, Bartuli, Andrea, Biasucci, Giacomo, Biolo, Gianni, Bonanni, Luca, Bonomo, Katia, Borghi, Claudio, Bossi, Antonio Carlo, Branchi, Adriana, Carubbi, Francesca, Cipollone, Francesco, Citroni, Nadia, Federici, Massimo, Ferri, Claudio, Fiorenza, Anna Maria, Giaccari, Andrea, Giorgino, Francesco, Guardamagna, Ornella, Iannuzzi, Arcangelo, Iughetti, Lorenzo, Lupattelli, Graziana, Mandraffino, Giuseppe, Marcucci, Rossella, Mombelli, Giuliana, Muntoni, Sandro, Pecchioli, Valerio, Pederiva, Cristina, Pipolo, Antonio, Pisciotta, Livia, Pujia, Arturo, Purrello, Francesco, Repetti, Elena, Rubba, Paolo, SabbÃ&nbsp, Carlo, Sampietro, Tiziana, Sarzani, Riccardo, Tagliabue, Milena Paola, Trenti, Chiara, Vigna, Giovanni Battista, Werba, Josà Pablo, Zambon, Sabina, Zenti, Maria Grazia, Montali, Anna, Noto, Davide, Fortunato, Giuliana, Grigore, Liliana, Del Ben, Maria, Maranghi, Marianna, Cefalã¹, A. Baldassarre, Buonuomo, Paola Sabrina, Capra, Maria Elena, Vinci, Pierandrea, D'Addato, Sergio, Galbiati, Stella, Nascimbeni, Fabio, Bucci, Marco, Spagnoli, Walter, Cardolini, Iris, Cervelli, Nazzareno, Emanuela, Colombo, Sun, Vinsin A., Laviola, Luigi, Bello, Francesca, Chiariello, Giuseppe, Predieri, Barbara, Siepi, Donatella, Saitta, Antonino, Giusti, Betti, Pavanello, Chiara, Lussu, Milena, Prati, Lucia, Banderali, Giuseppe, Balleari, Giulia, Montalcini, Tiziana, Scicali, Roberto, Gentile, Luigi, Gentile, Marco, Suppressa, Patrizia, Sbrana, Francesco, Cocci, Guido, Benso, Andrea, Negri, Emanuele Alberto, Ghirardello, Omar, Lorenzo, Vigo, Zambon, Alberto, Enzo, Bonora, Minicocci, Ilenia, Spina, Rossella, Orlando, Camilla, Di Taranto, Maria Donata, Casula, Manuela, Chiodo, Lorenzo, Manzato, Enzo, Tragni, Elena, Pirillo, Angela, Garlaschelli, Katia, Arca, Marcello, Averna, Maurizio, Bertolini, Stefano, Calandra, Sebastiano, Tarugi, Patrizia, Catapano, Alberico L., Catapano, Alberico Luigi, Pellegatta, Fabio, Angelico, Francesco, Bartuli, Andrea, Biasucci, Giacomo, Biolo, Gianni, Bonanni, Luca, Bonomo, Katia, Borghi, Claudio, Bossi, Antonio Carlo, Branchi, Adriana, Carubbi, Francesca, Cipollone, Francesco, Citroni, Nadia, Federici, Massimo, Ferri, Claudio, Fiorenza, Anna Maria, Giaccari, Andrea, Giorgino, Francesco, Guardamagna, Ornella, Iannuzzi, Arcangelo, Iughetti, Lorenzo, Lupattelli, Graziana, Mandraffino, Giuseppe, Marcucci, Rossella, Mombelli, Giuliana, Muntoni, Sandro, Pecchioli, Valerio, Pederiva, Cristina, Pipolo, Antonio, Pisciotta, Livia, Pujia, Arturo, Purrello, Francesco, Repetti, Elena, Rubba, Paolo, Sabbã , Carlo, Sampietro, Tiziana, Sarzani, Riccardo, Tagliabue, Milena Paola, Trenti, Chiara, Vigna, Giovanni Battista, Werba, Josã Pablo, Zambon, Sabina, Zenti, Maria Grazia, Montali, Anna, Noto, Davide, Fortunato, Giuliana, Grigore, Liliana, DEL BELLO, Francesca, Maranghi, Marianna, Cefalã¹, A. Baldassarre, Buonuomo, Paola Sabrina, Capra, Maria Elena, Vinci, Pierandrea, D'Addato, Sergio, Galbiati, Stella, Nascimbeni, Fabio, Bucci, Marco, Spagnoli, Walter, Cardolini, Iri, Cervelli, Nazzareno, Emanuela, Colombo, Sun, Vinsin A., Laviola, Luigi, Bello, Francesca, Chiariello, Giuseppe, Predieri, Barbara, Siepi, Donatella, Saitta, Antonino, Giusti, Betti, Pavanello, Chiara, Lussu, Milena, Prati, Lucia, Banderali, Giuseppe, Balleari, Giulia, Montalcini, Tiziana, Scicali, Roberto, Gentile, Luigi, Gentile, Marco, Suppressa, Patrizia, Sbrana, Francesco, Cocci, Guido, Benso, Andrea, Negri, Emanuele Alberto, Ghirardello, Omar, Lorenzo, Vigo, Zambon, Alberto, Enzo, Bonora, Minicocci, Ilenia, Spina, Rossella, Orlando, Camilla, Di Taranto, Maria Donata, Casula, Manuela, Chiodo, Lorenzo, Manzato, Enzo, Tragni, Elena, Sabbà, Carlo, Werba, Josè Pablo, Del Ben, Maria, Cefalù, A. Baldassarre, DI BELLO, Francesca, Pirillo, A., Garlaschelli, K., Arca, M., Averna, M., Bertolini, S., Calandra, S., Tarugi, P., Catapano, A., Pellegatta, F., Angelico, F., Bartuli, A., Biasucci, G., Biolo, G., Bonanni, L., Bonomo, K., Borghi, C., Bossi, A., Branchi, A., Carubbi, F., Cipollone, F., Citroni, N., Federici, M., Ferri, C., Fiorenza, A., Giaccari, A., Giorgino, F., Guardamagna, O., Iannuzzi, A., Iughetti, L., Lupattelli, G., Mandraffino, G., Marcucci, R., Mombelli, G., Muntoni, S., Pecchioli, V., Pederiva, C., Pipolo, A., Pisciotta, L., Pujia, A., Purrello, F., Repetti, E., Rubba, P., Sabbã , C., Sampietro, T., Sarzani, R., Tagliabue, M., Trenti, C., Vigna, G., Werba, J., Zambon, S., Zenti, M., Montali, A., Noto, D., Fortunato, G., Grigore, L., Del Ben, M., Maranghi, M., Cefalu', A., Buonuomo, P., Capra, M., Vinci, P., D'Addato, S., Galbiati, S., Nascimbeni, F., Bucci, M., Spagnoli, W., Cardolini, I., Cervelli, N., Emanuela, C., Sun, V., Laviola, L., Bello, F., Chiariello, G., Predieri, B., Siepi, D., Saitta, A., Giusti, B., Pavanello, C., Lussu, M., Prati, L., Banderali, G., Balleari, G., Montalcini, T., Scicali, R., Gentile, L., Gentile, M., Suppressa, P., Sbrana, F., Cocci, G., Benso, A., Negri, E., Ghirardello, O., Lorenzo, V., Zambon, A., Enzo, B., Minicocci, I., Spina, R., Orlando, C., Di Taranto, M., Casula, M., Chiodo, L., Manzato, E., Tragni, E., and Colombo, Emanuela

Subjects
0301 basic medicine, Apolipoprotein E, Candidate gene, Settore MED/09 - Medicina Interna, Databases, Factual, Apolipoprotein B, DNA Mutational Analysis, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Compound heterozygosity, PCSK9, 0302 clinical medicine, Risk Factors, Receptors, Genetics, Homozygote, Autosomal dominant trait, Pathogenic variants, General Medicine, Prognosis, APOB, LDLR, Cholesterol, Phenotype, Italy, Autosomal Recessive Hypercholesterolemia, Apolipoprotein B-100, lipids (amino acids, peptides, and proteins), Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, Preliminary Data, Genetic Markers, Familial hypercholesterolemiaLDLRPCSK9APOBPathogenic variants, Heterozygote, Biology, Pathogenic variant, LDL, Hyperlipoproteinemia Type II, 03 medical and health sciences, Databases, medicine, Internal Medicine, Humans, Genetic Predisposition to Disease, Factual, Settore MED/13 - ENDOCRINOLOGIA, medicine.disease, Atherosclerosis, 030104 developmental biology, Receptors, LDL, Mutation, biology.protein
Abstract

Background Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by elevated plasma levels of LDL-cholesterol that confers an increased risk of premature atherosclerotic cardiovascular disease. Early identification and treatment of FH patients can improve prognosis and reduce the burden of cardiovascular mortality. Aim of this study was to perform the mutational analysis of FH patients identified through a collaboration of 20 Lipid Clinics in Italy (LIPIGEN Study). Methods We recruited 1592 individuals with a clinical diagnosis of definite or probable FH according to the Dutch Lipid Clinic Network criteria. We performed a parallel sequencing of the major candidate genes for monogenic hypercholesterolemia (LDLR, APOB, PCSK9, APOE, LDLRAP1, STAP1). Results A total of 213 variants were detected in 1076 subjects. About 90% of them had a pathogenic or likely pathogenic variants. More than 94% of patients carried pathogenic variants in LDLR gene, 27 of which were novel. Pathogenic variants in APOB and PCSK9 were exceedingly rare. We found 4 true homozygotes and 5 putative compound heterozygotes for pathogenic variants in LDLR gene, as well as 5 double heterozygotes for LDLR/APOB pathogenic variants. Two patients were homozygous for pathogenic variants in LDLRAP1 gene resulting in autosomal recessive hypercholesterolemia. One patient was found to be heterozygous for the ApoE variant p.(Leu167del), known to confer an FH phenotype. Conclusions This study shows the molecular characteristics of the FH patients identified in Italy over the last two years. Full phenotypic characterization of these patients and cascade screening of family members is now in progress.

Published
2017

40. Clinical and biochemical characteristics of individuals with low cholesterol syndromes: A comparison between familial hypobetalipoproteinemia and familial combined hypolipidemia

Author

Alessia Di Costanzo, Angelo B. Cefalù, Laura D'Erasmo, Patrizia Tarugi, Maurizio Averna, Enza Di Leo, Vito Cantisani, Davide Noto, Rossella Spina, Luca Polito, Ilenia Minicocci, Marcello Arca, Di Costanzo, A., Di Leo, E., Noto, D., Cefalu', A., Minicocci, I., Polito, L., D'Erasmo, L., Cantisani, V., Spina, R., Tarugi, P., Averna, M., and Arca, M.

Subjects
0301 basic medicine, Male, Hepatic steatosis, Settore MED/09 - Medicina Interna, Apolipoprotein B, Endocrinology, Diabetes and Metabolism, 030204 cardiovascular system & hematology, medicine.disease_cause, ANGPTL3 gene, APOB gene, Familial combined hypolipidemia, Familial hypobetalipoproteinemia, HDL cholesterol, Low cholesterol syndromes, Hypobetalipoproteinemias, Exon, 0302 clinical medicine, ANGPTL3, Nutrition and Dietetic, Genetics, Mutation, Nutrition and Dietetics, biology, hepatic steatosis, Homozygote, Middle Aged, Phenotype, lipids (amino acids, peptides, and proteins), Female, Cardiology and Cardiovascular Medicine, familial combined hypolipidemia, familial hypobetalipoproteinemia, low cholesterol syndromes, medicine.medical_specialty, Heterozygote, Low cholesterol syndrome, Hepatic steatosi, 03 medical and health sciences, Internal medicine, Internal Medicine, medicine, Humans, Gene, Aged, Angiopoietin-Like Protein 3, Apolipoproteins B, business.industry, Heterozygote advantage, medicine.disease, 030104 developmental biology, Endocrinology, Angiopoietin-like Proteins, biology.protein, Steatosis, business
Abstract

Background The most frequent monogenic causes of low plasma cholesterol are familial hypobetalipoproteinemia (FHBL1) because of truncating mutations in apolipoprotein B coding gene (APOB) and familial combined hypolipidemia (FHBL2) due to loss-of-function mutations in ANGPTL3 gene. Objective A direct comparison of lipid phenotypes of these 2 conditions has never been carried out. In addition, although an increased prevalence of liver steatosis in FHBL1 has been consistently reported, the hepatic consequences of FHBL2 are not well established. Methods We investigated 350 subjects, 67 heterozygous carriers of APOB mutations, 63 carriers of the p.S17* mutation in ANGPTL3 (57 heterozygotes and 6 homozygotes), and 220 noncarrier normolipemic controls. Prevalence and degree of hepatic steatosis were assessed by ultrasonography. Results A steady decrease of low-density lipoprotein cholesterol levels were observed from heterozygous to homozygous FHBL2 and to FHBL1 individuals, with the lowest levels in heterozygous FHBL1 carrying truncating mutations in exons 1 to 25 of APOB (P for trend

Published
2017

41. Characterization of a mutant form of human apolipoprotein B (Thr26_Tyr27del) associated with familial hypobetalipoproteinemia

Author

Maurizio Averna, Davide Noto, Lucia Magnolo, Zemin Yao, Patrizia Tarugi, Sebastiano Calandra, Angelo B. Cefalù, Magnolo, L., Noto, D., Cefalù, A., Averna, M., Calandra, S., Yao, Z., and Tarugi, P.

Subjects
0301 basic medicine, Settore MED/09 - Medicina Interna, Time Factors, Apolipoprotein B-48 secretion, Apolipoprotein B, Mutant, DNA Mutational Analysis, Apolipoprotein B mutation, Apolipoprotein B-48 secretion, Hypobetalipoproteinemia, Proteasomal degradation, 030204 cardiovascular system & hematology, medicine.disease_cause, Endoplasmic Reticulum, Hypobetalipoproteinemias, chemistry.chemical_compound, 0302 clinical medicine, Proteasomal degradation, Proteolysi, Sequence Deletion, Mutation, biology, Medicine (all), Transfection, Proteasome Inhibitor, Phenotype, Biochemistry, Apolipoprotein B-100, lipids (amino acids, peptides, and proteins), Proteasome Inhibitors, Human, Heterozygote, Proteasome Endopeptidase Complex, Time Factor, Cycloheximide, digestive system, Cell Line, DNA Mutational Analysi, 03 medical and health sciences, medicine, Humans, Secretion, Genetic Predisposition to Disease, Molecular Biology, Endoplasmic reticulum, nutritional and metabolic diseases, Cell Biology, medicine.disease, Molecular biology, 030104 developmental biology, chemistry, Proteolysis, biology.protein, Hypobetalipoproteinemia, Apolipoprotein B mutation, Apolipoprotein B-48
Abstract

We have previously identified a deletion mutant of human apoB [apoB (Thr26_Tyr27del)] in a subject with primary hypobetalipoproteinemia. The present study determined the effect of Thr26_Tyr27del mutation on apoB secretion using transfected McA-RH7777 cells. Transient or stable transfection of apoB-48 containing the Thr26_Tyr27del mutation showed drastically reduced secretion of the mutant as compared to wild-type apoB-48. No lipoproteins containing the mutant apoB-48 were secreted into the medium. Incubation of transfected cells in a lipid-rich medium in the presence of cycloheximide showed rapid turnover of cell-associated mutant apoB-48 as compared to that of wild-type apoB-48. Immunofluorescence experiments showed that the mutant apoB-48 was mostly localized in the endoplasmic reticulum. Treatment with the proteasomal inhibitor MG132 markedly attenuated the turnover of cell-associated mutant apoB-48, whereas treatment with inhibitors of autophagosomal/lysosomal function (e.g. 3-MA or ammonium chloride) had no effect. Taken together, these results indicated that the defective secretion of the Thr26_Tyr27del mutant was associated with increased intracellular degradation of apoB through the proteasome-dependent pathway.

Published
2016

42. Association between familial hypobetalipoproteinemia and the risk of diabetes. Is this the other side of the cholesterol-diabetes connection? A systematic review of literature

Author

Patrizia Tarugi, Marcello Arca, Carlo M. Barbagallo, Maurizio Averna, Angelo B. Cefalù, Davide Noto, Noto, D., Arca, M., Tarugi, P., Cefalu', A., Barbagallo, C., and Averna, M.

Subjects
0301 basic medicine, Proband, Male, medicine.medical_specialty, Settore MED/09 - Medicina Interna, Apolipoprotein B, Endocrinology, Diabetes and Metabolism, Population, Prevalence, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Hypobetalipoproteinemias, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Diabetes Mellitus, Humans, Familial hypobetalipoproteinemia, Diabetes mellitus risk, education, education.field_of_study, biology, Cholesterol, business.industry, PCSK9, Statins, Statin, General Medicine, Cholesterol, LDL, medicine.disease, Familial hypobetalipoproteinemia-Cholesterol- Diabetes mellitus risk- Statins, 030104 developmental biology, chemistry, biology.protein, lipids (amino acids, peptides, and proteins), Female, business
Abstract

Statin therapy is beneficial in reducing LDL cholesterol (LDL-C) levels and cardiovascular events, but it is associated with the risk of incident diabetes mellitus (DM). Familial hypercholesterolemia (FH) is characterized by genetically determined high levels of plasma LDL-C and a low prevalence of DM. LDL-C levels seem then inversely correlated with prevalence of DM. Familial hypobetalipoproteinemia (FHBL) represents the genetic mirror of FH in terms of LDL-C levels, very low in subjects carrying mutations of APOB, PCSK9 (FHBL1) or ANGPTL3 (FHBL2). This review explores the hypothesis that FHBL might represent also the genetic mirror of FH in terms of prevalence of DM and that it is expected to be increased in FHBL in comparison with the general population. A systematic review of published literature on FHBL was made by searching PubMed (1980–2016) for articles presenting clinical data on FHBL probands and relatives. The standardized prevalence rates of DM in FHBL1 were similar to those of the reference population, with a prevalence rate of 8.2 and 9.2%, respectively, while FHBL2 showed a 4.9% prevalence of DM. In conclusion, low LDL-C levels of FHBL do not seem connected to DM as it happens in subjects undergoing statin therapy and the diabetogenic effect of statins has to be explained by mechanisms that do not rely exclusively on the reduced levels of LDL-C. The review also summarizes the published data on the effects of FHBL on insulin sensitivity and the relationships between FH, statin therapy, FHBL1 and intracellular cholesterol metabolism, evaluating possible diabetogenic pathways.

Published
2016

43. Microsomal triglyceride transfer protein gene mutations in Turkish children: A novel mutation and clinical follow up

Author

Maurizio Averna, Eda Özaydin, Gülşen Köse, Patrizia Tarugi, Ceyda Tuna Kırsaçlıoğlu, Mehmet Gündüz, Nevra Koç, Angelo B. Cefalù, Müge Atar, Gündüz, M., Özaydın, E., Atar, M., Koç, N., Kırsaçlıoğlu, C., Köse, G., Cefalù, A., Averna, M., and Tarugi, P.

Subjects
Male, 0301 basic medicine, Heterozygote, medicine.medical_specialty, Settore MED/09 - Medicina Interna, Turkey, Developmental delay, Developmental Disabilities, Turkish, 030204 cardiovascular system & hematology, Hepatic steatosi, medicine.disease_cause, Microsomal triglyceride transfer protein, 03 medical and health sciences, Exon, 0302 clinical medicine, Internal medicine, Humans, Medicine, Gene, Genetic Association Studies, Genetics, Mutation, ABL, biology, AbetalipoproteinemiaDevelopmental delayHepatic steatosisMicrosomal triglyceride transfer proteinTurkish, business.industry, Intron, Gastroenterology, Infant, Abetalipoproteinemia, medicine.disease, Introns, Fatty Liver, 030104 developmental biology, Endocrinology, biology.protein, Female, Steatosis, Carrier Proteins, business, Follow-Up Studies
Abstract

Abetalipoproteinemia (ABL; OMIM 200100) is a rare autosomal recessive disease that affects the absorption of dietary fats and fat soluble vitamins. Here, we describe the clinical and genetic characteristics of three patients with ABL. Two patients (patients 1 and 2) who were carriers of the c.398-399delAA mutation (previously known mutation) had developmental delay and hepatic steatosis developed at the age of five in patient 1. Patient 3 was the carrier of a novel mutation (g.10886-10902delAAGgtaagtttgtgttg in intron 3 and c.506A>T exon 5) in microsomal triglyceride transfer protein (MTP) gene and had hepatic steatosis.

Published
2016

44. Plasma non-cholesterol sterols in primary hypobetalipoproteinemia

Author

Maurizio Averna, Francesca Fayer, Davide Noto, Angelo B. Cefalù, Pin Yue, Gustav Schonfeld, Mariangela Mina, Patrizia Tarugi, Giacoma Barraco, Noto, D, Cefalu', AB, Barraco, G, Fayer, F, Mina', M, Yue, P, Tarugi, P, Schonfeld, G, and Averna, M

Subjects
Adult, medicine.medical_specialty, Settore MED/09 - Medicina Interna, Adolescent, Non-cholesterol sterol, behavioral disciplines and activities, Absorption, Hypobetalipoproteinemias, chemistry.chemical_compound, Hypolipemia, familial hypobetalipoproteinemia, non-cholesterol sterols, genetics, Plasma cholesterol, Internal medicine, mental disorders, Genetics, medicine, Humans, Familial hypobetalipoproteinemia, Intestinal Mucosa, Child, Aged, Aged, 80 and over, Family Health, Models, Genetic, Cholesterol, Familial Hypobetalipoproteinemia, Phytosterols, Middle Aged, medicine.disease, Sterol, Sterols, Phenotype, Endocrinology, chemistry, Biochemistry, Homogeneous, Mutation, Hypobetalipoproteinemia, Cardiology and Cardiovascular Medicine
Abstract

Primary hypobetalipoproteinemia (pHBL) is characterized by plasma cholesterol levels ApoB48, and FHBL harbouring as yet unknown molecular defects. Not linked FHBL kindred are not homogeneous in terms of plasma NCS levels. NCS cannot replace genetic HBL analysis.

Published
2011

45. Spectrum of mutations of the LPL gene identified in Italy in patients with severe hypertriglyceridemia

Author

Sebastiano Calandra, Stefano Bertolini, Patrizia Tarugi, Claudio Rabacchi, Livia Pisciotta, Maurizio Averna, Davide Noto, R. Fresa, Angelo B. Cefalù, Rabacchi, C., Pisciotta, L., Cefalù, A., Noto, D., Fresa, R., Tarugi, P., Averna, M., Bertolini, S., and Calandra, S.

Subjects
Male, Settore MED/09 - Medicina Interna, DNA Mutational Analysis, Familial chylomicronemia, Gene variants, Lipoprotein lipase, Pancreatitis, Primary hypertriglyceridemia, Compound heterozygosity, medicine.disease_cause, Severity of Illness Index, Tertiary Care Centers, chemistry.chemical_compound, Gene Frequency, Cardiology and Cardiovascular Medicine, Child, Mutation, Homozygote, Middle Aged, Phenotype, Italy, Child, Preschool, Female, Hyperlipoproteinemia Type I, Adult, medicine.medical_specialty, Gene variant, Heterozygote, Adolescent, Biology, Young Adult, Internal medicine, medicine, Lipolysis, Humans, Genetic Predisposition to Disease, Triglycerides, Aged, Pancreatiti, Triglyceride, Hypertriglyceridemia, Infant, Heterozygote advantage, medicine.disease, Lipoprotein Lipase, Endocrinology, chemistry, Biomarkers
Abstract

Background: Monogenic hypertriglyceridemia (HTG) may result from mutations in some genes which impair the intravascular lipolysis of triglyceride (TG)-rich lipoproteins mediated by the enzyme Lipoprotein lipase (LPL). Mutations in the LPL gene are the most frequent cause of monogenic HTG (familial chylomicronemia) with recessive transmission. Methods: The LPL gene was resequenced in 149 patients with severe HTG (TG>10mmol/L) and 106 patients with moderate HTG (TG>4.5 and

Published
2015

46. Exome sequencing in suspected monogenic dyslipidemias

Author

Sigrid W. Fouchier, Sekar Kathiresan, James G. Wilson, Marjorie Risman, Benjamin M. Neale, Catherine Boileau, Masa-aki Kawashiri, M. Mahdi Motazacker, Mathilde Varret, John J.P. Kastelein, Daniel J. Rader, G. Kees Hovingh, Clive R. Pullinger, Jorge F. Haller, Maurizio Averna, Stephen S. Rich, Angelo B. Cefalù, Isabelle Ruel, Jacques Genest, Nathan O. Stitziel, Rahul C. Deo, Namrata Gupta, Davide Noto, Deborah A. Nickerson, John P. Kane, Hiroshi Mabuchi, Jean-Pierre Rabès, Stacey Gabriel, Zuhier Awan, Mason W. Freeman, Deborah N. Farlow, Patrizia Tarugi, Atsushi Nohara, Mark J. Daly, Jay Shendure, Gina M. Peloso, Hayato Tada, Masakazu Yamagishi, Marianne Abifadel, Daniel B. Larach, ACS - Amsterdam Cardiovascular Sciences, Human Genetics, Vascular Medicine, Stitziel, N., Peloso, G., Abifadel, M., Cefalu, A., Fouchier, S., Motazacker, M., Tada, H., Larach, D., Awan, Z., Haller, J., Pullinger, C., Varret, M., Rabès, J., Noto, D., Tarugi, P., Kawashiri, M., Nohara, A., Yamagishi, M., Risman, M., Deo, R., Ruel, I., Shendure, J., Nickerson, D., Wilson, J., Rich, S., Gupta, N., Farlow, D., Neale, B., Daly, M., Kane, J., Freeman, M., Genest, J., Rader, D., Mabuchi, H., Kastelein, J., Hovingh, G., Averna, M., Gabriel, S., Boileau, C., and Kathiresan, S.

Subjects
Male, Settore MED/09 - Medicina Interna, Medical Biotechnology, DNA sequencing, exome, exome sequencing, genetics, human, lipids, mendelian genetics, Biology, Cardiorespiratory Medicine and Haematology, Novel gene, Gene mapping, Clinical Research, Genetics, 2.1 Biological and endogenous factors, Humans, genetics, Exome, human, Aetiology, Mendelian disorders, Genetics (clinical), Exome sequencing, Dyslipidemias, Inborn Errors, Human Genome, High-Throughput Nucleotide Sequencing, Atherosclerosis, Metabolism, Cardiovascular System & Hematology, lipids (amino acids, peptides, and proteins), Female, genetic, Cardiology and Cardiovascular Medicine, Metabolism, Inborn Errors
Abstract

Background— Exome sequencing is a promising tool for gene mapping in Mendelian disorders. We used this technique in an attempt to identify novel genes underlying monogenic dyslipidemias. Methods and Results— We performed exome sequencing on 213 selected family members from 41 kindreds with suspected Mendelian inheritance of extreme levels of low-density lipoprotein cholesterol (after candidate gene sequencing excluded known genetic causes for high low-density lipoprotein cholesterol families) or high-density lipoprotein cholesterol. We used standard analytic approaches to identify candidate variants and also assigned a polygenic score to each individual to account for their burden of common genetic variants known to influence lipid levels. In 9 families, we identified likely pathogenic variants in known lipid genes ( ABCA1 , APOB , APOE , LDLR, LIPA , and PCSK9 ); however, we were unable to identify obvious genetic etiologies in the remaining 32 families, despite follow-up analyses. We identified 3 factors that limited novel gene discovery: (1) imperfect sequencing coverage across the exome hid potentially causal variants; (2) large numbers of shared rare alleles within families obfuscated causal variant identification; and (3) individuals from 15% of families carried a significant burden of common lipid-related alleles, suggesting complex inheritance can masquerade as monogenic disease. Conclusions— We identified the genetic basis of disease in 9 of 41 families; however, none of these represented novel gene discoveries. Our results highlight the promise and limitations of exome sequencing as a discovery technique in suspected monogenic dyslipidemias. Considering the confounders identified may inform the design of future exome sequencing studies.

Published
2013

47. Familial combined hypolipidemia due to mutations in the ANGPTL3 gene

Author

Patrizia Tarugi, Maurizio Averna, Stefano Bertolini, Sebastiano Calandra, Calandra, Tarugi P, Averna M, and Bertolini S

Subjects
Genetics, Endothelial lipase, Mutation, Lipoprotein lipase, Very low-density lipoprotein, education.field_of_study, Settore MED/09 - Medicina Interna, Endocrinology, Diabetes and Metabolism, Population, ANGPTL3, ANGPTL8, endothelial lipase, familial combined hypolipidemia, HDL, LDL, lipoprotein lipase, Biology, Compound heterozygosity, medicine.disease_cause, medicine, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, education, ANGPTL3, ANGPTL8, endothelial lipase, familial combined hypolipidemia, HDL, LDL, lipoprotein lipase, Lipoprotein
Abstract

The role of ANGPTL3 in lipoprotein metabolism emerged from studies in a mutant mouse strain characterized by severe hypotriglyceridemia and carrying a loss-of-function (LOF) mutation of the ANGPTL3 gene. ANGPTL3 was found to inhibit lipoprotein lipase and endothelial lipase. Genome-wide association studies in humans demonstrated the association of ANGPTL3 variants with plasma triglyceride levels and LOF mutations of ANGPTL3 were found in hypotriglyceridemic subjects in population studies. Recently, individuals originally classified as affected by familial hypobetalipoproteinemia were found to be homozygotes/compound heterozygotes for rare LOF mutations of ANGPTL3. They show a striking reduction of all lipoprotein classes (VLDL, LDL and HDL), a condition defined as familial combined hypolipidemia. This disorder, transmitted as a recessive trait, does not seem to be associated with specific clinical manifestations, such as premature atherosclerosis or fatty liver disease.

Published
2013

48. Prevalence of ANGPTL3 and APOB gene mutations in subjects with combined hypolipidemia

Author

Mariangela Ditta, Pin Yue, Giovanni Battista Vigna, Elisa Pinotti, Angelo B. Cefalù, Patrizia Tarugi, Francesca Fayer, Sekar Kathiresan, Rossella Spina, Vincenza Valenti, Maurizio Averna, Davide Noto, Noto, D, Cefalù, A, Valenti, V, Fayer, F, Pinotti, E, Ditta, M, Spina, R, Vigna, G, Yue, P, Kathiresan, S, Tarugi, P, and Averna, M

Subjects
Male, Settore MED/09 - Medicina Interna, Apolipoprotein B, Gene mutation, Compound heterozygosity, medicine.disease_cause, Severity of Illness Index, Hypobetalipoproteinemias, chemistry.chemical_compound, Gene Frequency, 80 and over, Prevalence, Missense mutation, genetics, epidemiology, hypobetalipoproteinemia, lipoproteins, Adolescent, Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Angiopoietins, Apolipoproteins B, Biomarkers, Cholesterol, Cholesterol, HDL, Female, Genetic Predisposition to Disease, Heterozygote, Homozygote, Humans, Italy, Middle Aged, Missouri, Molecular Sequence Data, Phenotype, Young Adult, Codon, Nonsense, Mutation, Missense, Cardiology and Cardiovascular Medicine, Mutation, Human, medicine.medical_specialty, HDL, Socio-culturale, Angiopoietin, Biology, Internal medicine, medicine, Codon, Allele frequency, Angiopoietin-Like Protein 3, medicine.disease, Endocrinology, Angiopoietin-like Proteins, Nonsense, chemistry, Biological Marker, biology.protein, Hypobetalipoproteinemia, Missense
Abstract

Objective— Mutations of the ANGPTL3 gene have been associated with a novel form of primary hypobetalipoproteinemia, the combined hypolipidemia (cHLP), characterized by low total cholesterol and low HDL-cholesterol levels. The aim of this work is to define the role of ANGPTL3 gene as determinant of the combined hypolipidemia phenotype in 2 large cohorts of 913 among American and Italian subjects with primary hypobetalipoproteinemia (total cholesterol Methods and Results— The combined hypolipidemia cut-offs were chosen according to total cholesterol and HDL-cholesterol levels reported in the ANGPTL3 kindred described to date: total cholesterol levels, ANGPTL3 and APOB genes. We identified nonsense and/or missense mutations in ANGPTL3 gene in 8 subjects; no mutations of the APOB gene were found. Mutated ANGPTL3 homozygous/compound heterozygous subjects showed a more severe biochemical phenotype compared to heterozygous or ANGPTL3 negative subjects, although ANGPTL3 heterozygotes did not differ from ANGPTL3 negative subjects. Conclusion— These results demonstrated that in a cohort of subjects with severe primary hypobetalipoproteinemia the prevalence of ANGPTL3 gene mutations responsible for a combined hypolipidemia phenotype is about 10%, whereas mutations of APOB gene are absent.

Published
2012

49. Lipid and apoprotein composition of HDL in partial or complete CETP deficiency

Author

Patrizia Tarugi, Maurizio Averna, Peter M. Nilsson, Gregor Dernick, Elisabeth von der Mark, Angelo B. Cefalù, Eric J. Niesor, Laura Calabresi, Niesor, E, von der Mark, E, Calabresi, L, Averna, M, Cefalù, A, Tarugi, P, Nilsson, P, and Dernick, G

Subjects
Settore MED/09 - Medicina Interna, Apolipoprotein B, Cholesterol Ester Transfer Protein, medicine.disease_cause, reverse phase protein array, chemistry.chemical_compound, Exon, Mutation, biology, Homozygote, scavenger receptor class B1, size exclusion chromatography, Lipid, Cholesteryl ester transfer protein, Lipids, torcetrapib, Apolipoprotein, Biochemistry, ELISA, lipids (amino acids, peptides, and proteins), hyperalphalipoproteinemia, Cardiology and Cardiovascular Medicine, Lipoproteins, HDL, Human, dalcetrapib, medicine.medical_specialty, Heterozygote, Dalcetrapib, Hypercholesterolemia, apolipoprotein, high-density lipoprotein, Internal medicine, Cholesterylester transfer protein, medicine, Animals, Humans, Pharmacology, business.industry, Animal, Point mutation, Cholesterol, HDL, Torcetrapib, nutritional and metabolic diseases, Lipid Metabolism, Cholesterol Ester Transfer Proteins, carbohydrates (lipids), Disease Models, Animal, Endocrinology, Apolipoproteins, chemistry, biology.protein, business, Lipoprotein
Abstract

Hyperalphalipoproteinemia, as observed in patients who are either homozygous or heterozygous for cholesteryl ester transfer protein (CETP) deficiency, has been shown to be associated with striking changes in apolipoprotein size distribution, namely, of high-density lipoprotein (HDL) and HDL-like particles. We compared the effect of varying degrees of CETP activity on the HDL apolipoprotein profile in Caucasian CETP-deficient subjects and following pharmacological decrease in CETP activity, using Size Exclusion Chromatography followed by Reverse Phase Protein Array (SEC RPA). The main HDL-associated apolipoproteins (Apo), i.e. ApoA-I, ApoA-II, ApoC-I, and ApoC-III, co-eluted with the HDL peak. The presence of a HDL-like peak migrating between the ApoB-LDL and ApoA-I-HDL was identified in a Caucasian patient with homozygosity for a point mutation in exon 2 of the CETP gene (c.109 C > T) resulting in a premature termination codon (R37X) and complete CETP deficiency. This HDL-like peak was not observed either in healthy volunteers treated with the CETP modulator dalcetrapib, patients heterozygous for the same mutation, or in patients heterozygous with G165X mutations. SEC RPA offers the possibility to investigate the distribution of a large number of apolipoproteins simultaneously under non-denaturing separation in normal and dyslipidemic subjects. This is only limited by the availability of antibodies against specific apolipoproteins to be investigated.

Published
2012

50. Novel mutation in the ApoB Gene (Apo B-15.56): A Case Report

Author

Patrizia Tarugi, Antonio Vittorino Gaddi, Marilisa Bove, Lucio Carnevali, Arrigo F G Cicero, Bove M., Carnevali L., Cicero A., Tarugi P., and Gaddi A.

Subjects
medicine.medical_specialty, Apolipoprotein B, Population, Genetic mutation, QH426-470, Exon, Insulin resistance, apolipoprotein b (apo-b), Internal medicine, medicine, Genetics, Familial hypobetalipoproteinemia, metabolic syndrome (ms), education, familial hypobetalipoproteinemia (fhbl), Genetics (clinical), Metabolic Syndrome, education.field_of_study, Apolipoprotein B (Apo-B), Familial hypobetalipoproteinemia (FHBL), Metabolic Syndrome (MS), biology, Fatty liver, Genetic disorder, medicine.disease, Obesity, Endocrinology, biology.protein, lipids (amino acids, peptides, and proteins), Metabolic syndrome
Abstract

Novel Mutation in theApobGene (Apo B-15.56): A Case ReportFamilial hypobetalipoproteinemia (FHBL) is a rare co-dominant genetic disorder characterized by decrease of plasma low density lipoprotein-cholesterol (LDL-c) or apolipoprotein B (Apo-B) equal to or less than the 5thpercentile for the population. We describe a 48-year-old male who presented with fatty liver disease (FLD), insulin resistance (IR), obesity and hypertension. Our patient thus met the latest diagnostic criteria of the metabolic syndrome (MS) proposed by the Adult Treatment Panel and the International Diabetes Federation. However, he had very low plasma concentration of LDL-c and Apo-B. DNA sequencing showed that he and two first-degree relatives affected by obesity and mild IR were heterozygous for a single nucleotide deletion on exon 15 of theAPOBgene, which was predicted to form a truncated Apo-B designated Apo B-15.56.

Published
2010

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