Sitosterolemia: Diagnosis, Metabolic and Hematological Abnormalities, Cardiovascular Disease and Management

Author(s): Jose María Bastida*, María Luisa Girós, Rocío Benito, Kamila Janusz, Jesús María Hernández-Rivas, José Ramón González-Porras

Journal Name: Current Medicinal Chemistry

Volume 26 , Issue 37 , 2019


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Abstract:

Sitosterolemia is a recessive inherited metabolic disorder of unknown prevalence, characterized by increased levels of plasma plant sterols. It is caused by 28 and 31 variants in ABCG5 and ABCG8 genes, respectively, and is characterized by a predisposition to hyperabsorption and accumulation of toxic levels of plant sterols in plasma. Its clinical picture is extremely heterogeneous. The main clinical features are tendinous and cutaneous xanthomas, arthritis or arthralgia, premature cardiovascular disease and atherosclerosis. These characteristics are shared with familial hypercholesterolemia (FH), making it possible for sitosterolemia to be misdiagnosed as homozygous FH, especially in pediatric patients. In such cases, a specific chromatography-based laboratory method is essential to differentiate sitosterol and cholesterol. Hematological abnormalities (hemolytic anemia and macrothrombocytopenia) may be present in 25-35% of patients, in whom it is usually associated with the main clinical features, as occurs in the 70% of the cases. In this context, the peripheral blood smear is essential and reveals giant platelets and stomatocytes. Only 21 causative variants in ABCG5/ABCG8 are associated with macrothrombocytopenia. Most physicians still do not recognize these hematological abnormalities or relate them to sitosterolemia. Patients may suffer long-term misdiagnosis of immune thrombocytopenia and be at high risk of receiving harmful therapies or of not benefitting from a low-cholesterol diet and/or from the gold standard treatment with ezetimibe. This drug reduces the levels of plasma plant sterols, provokes regression of xanthomas, and can alleviate hematological abnormalities. Finally, to identify genetic defects, recent advances in high-throughput sequencing, especially in the use of targeted sequencing of pre-specified genes, have begun to be incorporated in the first-line approach in the field of genetic disorders.

Keywords: Blood platelet disorders, sitosterol, macrothrombocytopenia, high-throughput nucleotide sequencing, genetic testing, hypercholesterolemia.

[1]
Bhattacharyya, A.K.; Connor, W.E. Beta-sitosterolemia and xanthomatosis. A newly described lipid storage disease in two sisters. J. Clin. Invest., 1974, 53(4), 1033-1043.
[http://dx.doi.org/10.1172/JCI107640] [PMID: 4360855]
[2]
Patel, S.B.; Salen, G.; Hidaka, H.; Kwiterovich, P.O.; Stalenhoef, A.F.; Miettinen, T.A.; Grundy, S.M.; Lee, M.H.; Rubenstein, J.S.; Polymeropoulos, M.H.; Brownstein, M.J. Mapping a gene involved in regulating dietary cholesterol absorption. The sitosterolemia locus is found at chromosome 2p21. J. Clin. Invest., 1998, 102(5), 1041-1044.
[http://dx.doi.org/10.1172/JCI3963] [PMID: 9727073]
[3]
Berge, K.E.; Tian, H.; Graf, G.A.; Yu, L.; Grishin, N.V.; Schultz, J.; Kwiterovich, P.; Shan, B.; Barnes, R.; Hobbs, H.H. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science, 2000, 290(5497), 1771-1775.
[http://dx.doi.org/10.1126/science.290.5497.1771] [PMID: 11099417]
[4]
Lee, M.H.; Lu, K.; Hazard, S.; Yu, H.; Shulenin, S.; Hidaka, H.; Kojima, H.; Allikmets, R.; Sakuma, N.; Pegoraro, R.; Srivastava, A.K.; Salen, G.; Dean, M.; Patel, S.B. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat. Genet., 2001, 27(1), 79-83.
[http://dx.doi.org/10.1038/83799] [PMID: 11138003]
[5]
Hubacek, J.A.; Berge, K.E.; Cohen, J.C.; Hobbs, H.H. Mutations in ATP-cassette binding proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia. Hum. Mutat., 2001, 18(4), 359-360.
[http://dx.doi.org/10.1002/humu.1206] [PMID: 11668628]
[6]
Kidambi, S.; Patel, S.B. Sitosterolaemia: pathophysiology, clinical presentation and laboratory diagnosis. J. Clin. Pathol., 2008, 61(5), 588-594.
[http://dx.doi.org/10.1136/jcp.2007.049775] [PMID: 18441155]
[7]
Lu, K.; Lee, M.H.; Hazard, S.; Brooks-Wilson, A.; Hidaka, H.; Kojima, H.; Ose, L.; Stalenhoef, A.F.; Mietinnen, T.; Bjorkhem, I.; Bruckert, E.; Pandya, A.; Brewer, H.B. Jr.; Salen, G.; Dean, M.; Srivastava, A.; Patel, S.B. Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively. Am. J. Hum. Genet., 2001, 69(2), 278-290.
[http://dx.doi.org/10.1086/321294] [PMID: 11452359]
[8]
Yoo, E.G. Sitosterolemia: a review and update of pathophysiology, clinical spectrum, diagnosis, and management. Ann. Pediatr. Endocrinol. Metab., 2016, 21(1), 7-14.
[http://dx.doi.org/10.6065/apem.2016.21.1.7] [PMID: 27104173]
[9]
Weingärtner, O.; Teupser, D.; Patel, S.B. The atherogenicity of plant sterols: the evidence from genetics to clinical trials. J. AOAC Int., 2015, 98(3), 742-749.
[http://dx.doi.org/10.5740/jaoacint.SGEWeingartner] [PMID: 25942705]
[10]
Escolà-Gil, J.C.; Quesada, H.; Julve, J.; Martín-Campos, J.M.; Cedó, L.; Blanco-Vaca, F. Sitosterolemia: diagnosis, investigation, and management. Curr. Atheroscler. Rep., 2014, 16(7), 424.
[http://dx.doi.org/10.1007/s11883-014-0424-2] [PMID: 24821603]
[11]
McDaniel, A.L.; Alger, H.M.; Sawyer, J.K.; Kelley, K.L.; Kock, N.D.; Brown, J.M.; Temel, R.E.; Rudel, L.L. Phytosterol feeding causes toxicity in ABCG5/G8 knockout mice. Am. J. Pathol., 2013, 182(4), 1131-1138.
[http://dx.doi.org/10.1016/j.ajpath.2012.12.014] [PMID: 23380580]
[12]
Tzavella, E.; Hatzimichael, E.; Kostara, C.; Bairaktari, E.; Elisaf, M.; Tsimihodimos, V. Sitosterolemia: A multifaceted metabolic disorder with important clinical consequences. J. Clin. Lipidol., 2017, 11(4), 1095-1100.
[http://dx.doi.org/10.1016/j.jacl.2017.04.116] [PMID: 28545928]
[13]
Rees, D.C.; Iolascon, A.; Carella, M.; O’marcaigh, A.S.; Kendra, J.R.; Jowitt, S.N.; Wales, J.K.; Vora, A.; Makris, M.; Manning, N.; Nicolaou, A.; Fisher, J.; Mann, A.; Machin, S.J.; Clayton, P.T.; Gasparini, P.; Stewart, G.W. Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia. Br. J. Haematol., 2005, 130(2), 297-309.
[http://dx.doi.org/10.1111/j.1365-2141.2005.05599.x] [PMID: 16029460]
[14]
Ono, S.; Matsuda, J.; Saito, A.; Yamamoto, T.; Fujimoto, W.; Shimizu, H.; Dateki, S.; Ouchi, K. A case of sitosterolemia due to compound heterozygous mutations in ABCG5: clinical features and treatment outcomes obtained with colestimide and ezetimibe. Clin. Pediatr. Endocrinol., 2017, 26(1), 17-23.
[http://dx.doi.org/10.1297/cpe.26.17] [PMID: 28203044]
[15]
Renner, C.; Connor, W.E.; Steiner, R.D. Sitosterolemia presenting as pseudohomozygous familial hypercholesterolemia. Clin. Med. Res., 2016, 14(2), 103-108.
[http://dx.doi.org/10.3121/cmr.2016.1294] [PMID: 27231115]
[16]
Wang, G.; Cao, L.; Wang, Z.; Jiang, M.; Sun, X.; Bai, X.; Ruan, C. Macrothrombocytopenia/stomatocytosis specially associated with phytosterolemia. Clin. Appl. Thromb. Hemost., 2012, 18(6), 582-587.
[http://dx.doi.org/10.1177/1076029611435090] [PMID: 22297561]
[17]
Niu, D.M.; Chong, K.W.; Hsu, J.H.; Wu, T.J.; Yu, H.C.; Huang, C.H.; Lo, M.Y.; Kwok, C.F.; Kratz, L.E.; Ho, L.T. Clinical observations, molecular genetic analysis, and treatment of sitosterolemia in infants and children. J. Inherit. Metab. Dis., 2010, 33(4), 437-443.
[http://dx.doi.org/10.1007/s10545-010-9126-2] [PMID: 20521169]
[18]
Kamelska, A.M.; Pietrzak-Fiećko, R.; Bryl, K. Variation of the cholesterol content in breast milk during 10 days collection at early stages of lactation. Acta Biochim. Pol., 2012, 59(2), 243-247.
[http://dx.doi.org/10.18388/abp.2012_2145] [PMID: 22540113]
[19]
Buonuomo, P.S.; Iughetti, L.; Pisciotta, L.; Rabacchi, C.; Papadia, F.; Bruzzi, P.; Tummolo, A.; Bartuli, A.; Cortese, C.; Bertolini, S.; Calandra, S. Timely diagnosis of sitosterolemia by next generation sequencing in two children with severe hypercholesterolemia. Atherosclerosis, 2017, 262, 71-77.
[http://dx.doi.org/10.1016/j.atherosclerosis.2017.05.002] [PMID: 28521186]
[20]
Wang, W.; Jiang, L.; Chen, P.P.; Wu, Y.; Su, P.Y.; Wang, L.Y. A case of sitosterolemia misdiagnosed as familial hypercholesterolemia: A 4-year follow-up. J. Clin. Lipidol., 2018, 12(1), 236-239.
[http://dx.doi.org/10.1016/j.jacl.2017.10.008] [PMID: 29246730]
[21]
Oosterveer, D.M.; Versmissen, J.; Yazdanpanah, M.; Hamza, T.H.; Sijbrands, E.J. Differences in characteristics and risk of cardiovascular disease in familial hypercholesterolemia patients with and without tendon xanthomas: a systematic review and meta-analysis. Atherosclerosis, 2009, 207(2), 311-317.
[http://dx.doi.org/10.1016/j.atherosclerosis.2009.04.009] [PMID: 19439299]
[22]
Menotti, A.; Puddu, P.E.; Lanti, M.; Maiani, G.; Fidanza, F. Cardiovascular risk factors predict survival in middle-aged men during 50 years. Eur. J. Intern. Med., 2013, 24(1), 67-74.
[http://dx.doi.org/10.1016/j.ejim.2012.08.004] [PMID: 22954458]
[23]
Wang, Z.; Cao, L.; Su, Y.; Wang, G.; Wang, R.; Yu, Z.; Bai, X.; Ruan, C. Specific macrothrombocytopenia/hemolytic anemia associated with sitosterolemia. Am. J. Hematol., 2014, 89(3), 320-324.
[http://dx.doi.org/10.1002/ajh.23619] [PMID: 24166850]
[24]
Stewart, G.W.; Lloyd, J.; Pegel, K. Mediterranean stomato-cytosis/macrothrombocytopenia: update from Adelaide, Australia. Br. J. Haematol., 2006, 132(5), 660-661.
[http://dx.doi.org/10.1111/j.1365-2141.2006.05973.x] [PMID: 16445847]
[25]
Wang, G.; Wang, Z.; Liang, J.; Cao, L.; Bai, X.; Ruan, C. A phytosterolemia patient presenting exclusively with macrothrombocytopenia and stomatocytic hemolysis. Acta Haematol., 2011, 126(2), 95-98.
[http://dx.doi.org/10.1159/000327248] [PMID: 21576934]
[26]
Neff, A.T. Sitosterolemia’s stomatocytosis and macrothrombocytopenia. Blood, 2012, 120(22), 4283.
[http://dx.doi.org/10.1182/blood-2012-06-429449] [PMID: 23310983]
[27]
Keller, S.; Prechtl, D.; Aslanidis, C.; Ceglarek, U.; Thiery, J.; Schmitz, G.; Jahreis, G. Increased plasma plant sterol concentrations and a heterozygous amino acid exchange in ATP binding cassette transporter ABCG5: a case report. Eur. J. Med. Genet., 2011, 54(4), e458-e460.
[http://dx.doi.org/10.1016/j.ejmg.2011.05.003] [PMID: 21664501]
[28]
Bastida, J.M.; Del Rey, M.; Revilla, N.; Benito, R.; Perez-Andrés, M.; González, B.; Riesco, S.; Janusz, K.; Padilla, J.; Hortal Benito-Sendin, A.; Bueno, D.; Blanco, E.; Hernández-Rivas, M.; Vicente, V.; Rivera, J.; González-Porras, R.; Lozano, M.L. Wiskott-Aldrich syndrome in a child presenting with macrothrombocytopenia. Platelets, 2017, 28(4), 417-420.
[http://dx.doi.org/10.1080/09537104.2016.1246715] [PMID: 27885891]
[29]
Balduini, C.L.; Savoia, A.; Seri, M. Inherited thrombocytopenias frequently diagnosed in adults. J. Thromb. Haemost., 2013, 11(6), 1006-1019.
[http://dx.doi.org/10.1111/jth.12196] [PMID: 23510089]
[30]
Bastida, J.M.; Benito, R.; Janusz, K.; Díez-Campelo, M.; Hernández-Sánchez, J.M.; Marcellini, S.; Girós, M.; Rivera, J.; Lozano, M.L.; Hortal, A.; Hernández-Rivas, J.M.; González-Porras, J.R. Two novel variants of the ABCG5 gene cause xanthelasmas and macrothrombocytopenia: a brief review of hematologic abnormalities of sitosterolemia. J. Thromb. Haemost., 2017, 15(9), 1859-1866.
[http://dx.doi.org/10.1111/jth.13777] [PMID: 28696550]
[31]
Kanaji, T.; Kanaji, S.; Montgomery, R.R.; Patel, S.B.; Newman, P.J. Platelet hyperreactivity explains the bleeding abnormality and macrothrombocytopenia in a murine model of sitosterolemia. Blood, 2013, 122(15), 2732-2742.
[http://dx.doi.org/10.1182/blood-2013-06-510461] [PMID: 23926302]
[32]
Chase, T.H.; Lyons, B.L.; Bronson, R.T.; Foreman, O.; Donahue, L.R.; Burzenski, L.M.; Gott, B.; Lane, P.; Harris, B.; Ceglarek, U.; Thiery, J.; Wittenburg, H.; Thon, J.N.; Italiano, J.E. Jr.; Johnson, K.R.; Shultz, L.D. The mouse mutation “thrombocytopenia and cardiomyopathy” (trac) disrupts Abcg5: a spontaneous single gene model for human hereditary phytosterolemia/sitosterolemia. Blood, 2010, 115(6), 1267-1276.
[http://dx.doi.org/10.1182/blood-2009-05-219808] [PMID: 19846887]
[33]
Su, Y.; Wang, Z.; Yang, H.; Cao, L.; Liu, F.; Bai, X.; Ruan, C. Clinical and molecular genetic analysis of a family with sitosterolemia and co-existing erythrocyte and platelet abnormalities. Haematologica, 2006, 91(10), 1392-1395.
[PMID: 17018391]
[34]
Kawamura, R.; Saiki, H.; Tada, H.; Hata, A. Acute myocardial infarction in a 25-year-old woman with sitosterolemia. J. Clin. Lipidol., 2018, 12(1), 246-249.
[http://dx.doi.org/10.1016/j.jacl.2017.10.017] [PMID: 29174072]
[35]
Othman, R.A.; Myrie, S.B.; Jones, P.J. Non-cholesterol sterols and cholesterol metabolism in sitosterolemia. Atherosclerosis, 2013, 231(2), 291-299.
[http://dx.doi.org/10.1016/j.atherosclerosis.2013.09.038] [PMID: 24267242]
[36]
Sabeva, N.S.; McPhaul, C.M.; Li, X.; Cory, T.J.; Feola, D.J.; Graf, G.A. Phytosterols differentially influence ABC transporter expression, cholesterol efflux and inflammatory cytokine secretion in macrophage foam cells. J. Nutr. Biochem., 2011, 22(8), 777-783.
[http://dx.doi.org/10.1016/j.jnutbio.2010.07.002] [PMID: 21111593]
[37]
Kolovou, G.; Voudris, V.; Drogari, E.; Palatianos, G.; Cokkinos, D.V. Coronary bypass grafts in a young girl with sitosterolemia. Eur. Heart J., 1996, 17(6), 965-966.
[http://dx.doi.org/10.1093/oxfordjournals.eurheartj.a014983] [PMID: 8781841]
[38]
Hansel, B.; Carrié, A.; Brun-Druc, N.; Leclert, G.; Chantepie, S.; Coiffard, A.S.; Kahn, J.F.; Chapman, M.J.; Bruckert, E. Premature atherosclerosis is not systematic in phytosterolemic patients: severe hypercholesterolemia as a confounding factor in five subjects. Atherosclerosis, 2014, 234(1), 162-168.
[http://dx.doi.org/10.1016/j.atherosclerosis.2014.02.030] [PMID: 24657386]
[39]
Goodyer, M.; Lovey, J.; Menétrey, M.J. Peripheral blood features of phytosterolaemia. Br. J. Haematol., 2015, 171(5), 669.
[http://dx.doi.org/10.1111/bjh.13626] [PMID: 26256107]
[40]
Kaya, Z.; Niu, D.M.; Yorulmaz, A.; Tekin, A.; Gürsel, T. A novel mutation of ABCG5 gene in a Turkish boy with phytosterolemia presenting with macrotrombocytopenia and stomatocytosis. Pediatr. Blood Cancer, 2014, 61(8), 1457-1459.
[http://dx.doi.org/10.1002/pbc.24934] [PMID: 24623560]
[41]
Greinacher, A.; Pecci, A.; Kunishima, S.; Althaus, K.; Nurden, P.; Balduini, C.L.; Bakchoul, T. Diagnosis of inherited platelet disorders on a blood smear: a tool to facilitate worldwide diagnosis of platelet disorders. J. Thromb. Haemost., 2017, 15(7), 1511-1521.
[http://dx.doi.org/10.1111/jth.13729] [PMID: 28457011]
[42]
Bastida Bermejo, J.M.; Hernández-Rivas, J.M.; González-Porras, J.R. Novel approaches for diagnosing inherited platelet disorders. Med. Clin. (Barc.), 2017, 148(2), 71-77.
[http://dx.doi.org/10.1016/j.medcli.2016.09.014] [PMID: 28218058]
[43]
Graf, G.A.; Cohen, J.C.; Hobbs, H.H. Missense mutations in ABCG5 and ABCG8 disrupt heterodimerization and trafficking. J. Biol. Chem., 2004, 279(23), 24881-24888.
[http://dx.doi.org/10.1074/jbc.M402634200] [PMID: 15054092]
[44]
Togo, M.; Toda, T.; Nguyen, L.A.; Kubota, S.; Tsukamoto, K.; Satoh, H.; Hara, M.; Iso-o, N.; Noto, H.; Kimura, S.; Nakahara, K.; Seyama, Y.; Hashimoto, Y. Genetic analysis of phytosterolaemia. J. Inherit. Metab. Dis., 2001, 24(1), 43-50.
[http://dx.doi.org/10.1023/A:1005650605042] [PMID: 11286381]
[45]
Heimerl, S.; Langmann, T.; Moehle, C.; Mauerer, R.; Dean, M.; Beil, F.U.; von Bergmann, K.; Schmitz, G. Mutations in the human ATP-binding cassette transporters ABCG5 and ABCG8 in sitosterolemia. Hum. Mutat., 2002, 20(2), 151.
[http://dx.doi.org/10.1002/humu.9047] [PMID: 12124998]
[46]
Kratz, M.; Kannenberg, F.; Gramenz, E.; Berning, B.; Trautwein, E.; Assmann, G.; Rust, S. Similar serum plant sterol responses of human subjects heterozygous for a mutation causing sitosterolemia and controls to diets enriched in plant sterols or stanols. Eur. J. Clin. Nutr., 2007, 61(7), 896-905.
[http://dx.doi.org/10.1038/sj.ejcn.1602598] [PMID: 17228349]
[47]
Bastida, J.M.; Lozano, M.L.; Benito, R.; Janusz, K.; Palma-Barqueros, V.; Del Rey, M.; Hernández-Sánchez, J.M.; Riesco, S.; Bermejo, N.; González-García, H.; Rodriguez-Alén, A.; Aguilar, C.; Sevivas, T.; López-Fernández, M.F.; Marneth, A.E.; van der Reijden, B.A.; Morgan, N.V.; Watson, S.P.; Vicente, V.; Hernández-Rivas, J.M.; Rivera, J.; González-Porras, J.R. Introducing high-throughput sequencing into mainstream genetic diagnosis practice in inherited platelet disorders. Haematologica, 2018, 103(1), 148-162.
[http://dx.doi.org/10.3324/haematol.2017.171132] [PMID: 28983057]
[48]
Bastida, J.M.; González-Porras, J.R.; Jiménez, C.; Benito, R.; Ordoñez, G.R.; Álvarez-Román, M.T.; Fontecha, M.E.; Janusz, K.; Castillo, D.; Fisac, R.M.; García-Frade, L.J.; Aguilar, C.; Martínez, M.P.; Bermejo, N.; Herrero, S.; Balanzategui, A.; Martin-Antorán, J.M.; Ramos, R.; Cebeiro, M.J.; Pardal, E.; Aguilera, C.; Pérez-Gutierrez, B.; Prieto, M.; Riesco, S.; Mendoza, M.C.; Benito, A.; Hortal Benito-Sendin, A.; Jiménez-Yuste, V.; Hernández-Rivas, J.M.; García-Sanz, R.; González-Díaz, M.; Sarasquete, M.E. Application of a molecular diagnostic algorithm for haemophilia A and B using next-generation sequencing of entire F8, F9 and VWF genes. Thromb. Haemost., 2017, 117(1), 66-74.
[http://dx.doi.org/10.1160/TH16-05-0375] [PMID: 27734074]
[49]
Bastida, J.M.; Del Rey, M.; Lozano, M.L.; Sarasquete, M.E.; Benito, R.; Fontecha, M.E.; Fisac, R.; García-Frade, L.J.; Aguilar, C.; Martínez, M.P.; Pardal, E.; Aguilera, C.; Pérez, B.; Ramos, R.; Cardesa, M.R.; Martin-Antorán, J.M.; Silvestre, L.A.; Cebeira, M.J.; Bermejo, N.; Riesco, S.; Mendoza, M.C.; García-Sanz, R.; González-Díaz, M.; Hernández-Rivas, J.M.; González-Porras, J.R. Design and application of a 23-gene panel by next-generation sequencing for inherited coagulation bleeding disorders. Haemophilia, 2016, 22(4), 590-597.
[http://dx.doi.org/10.1111/hae.12908] [PMID: 26879396]
[50]
Nurden, A.T.; Nurden, P. High-throughput sequencing for rapid diagnosis of inherited platelet disorders: a case for a European consensus. Haematologica, 2018, 103(1), 6-8.
[http://dx.doi.org/10.3324/haematol.2017.182295] [PMID: 29290630]
[51]
Salen, G.; Starc, T.; Sisk, C.M.; Patel, S.B. Intestinal cholesterol absorption inhibitor ezetimibe added to cholestyramine for sitosterolemia and xanthomatosis. Gastroenterology, 2006, 130(6), 1853-1857.
[http://dx.doi.org/10.1053/j.gastro.2006.02.027] [PMID: 16697747]
[52]
Othman, R.A.; Myrie, S.B.; Mymin, D.; Merkens, L.S.; Roullet, J.B.; Steiner, R.D.; Jones, P.J. Ezetimibe reduces plant sterol accumulation and favorably increases platelet count in sitosterolemia. J. Pediatr., 2015, 166(1), 125-131.
[http://dx.doi.org/10.1016/j.jpeds.2014.08.069] [PMID: 25444527]
[53]
Quintás-Cardama, A.; McCarthy, J.J. Long-term follow-up of a patient with sitosterolemia and hemolytic anemia with excellent response to ezetimibe. J. Genet. Disord. Genet. Rep., 2013, 2, 1.
[54]
Lozano, M.L.; Cook, A.; Bastida, J.M.; Paul, D.S.; Iruin, G.; Cid, A.R.; Adan-Pedroso, R.; Ramón González-Porras, J.; Hernández-Rivas, J.M.; Fletcher, S.J.; Johnson, B.; Morgan, N.; Ferrer-Marin, F.; Vicente, V.; Sondek, J.; Watson, S.P.; Bergmeier, W.; Rivera, J. Novel mutations in RASGRP2, which encodes CalDAG-GEFI, abrogate Rap1 activation, causing platelet dysfunction. Blood, 2016, 128(9), 1282-1289.
[http://dx.doi.org/10.1182/blood-2015-11-683102] [PMID: 27235135]
[55]
Sevivas, T.; Bastida, J.M.; Paul, D.S.; Caparros, E.; Palma-Barqueros, V.; Coucelo, M.; Marques, D.; Ferrer-Marín, F.; González-Porras, J.R.; Vicente, V.; Hernández-Rivas, J.M.; Watson, S.P.; Lozano, M.L.; Bergmeier, W.; Rivera, J. Identification of two novel mutations in RASGRP2 affecting platelet CalDAG-GEFI expression and function in patients with bleeding diathesis. Platelets, 2017, 1-4.
[http://dx.doi.org/10.1080/09537104.2017.1336214] [PMID: 28762304]


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VOLUME: 26
ISSUE: 37
Year: 2019
Published on: 17 December, 2019
Page: [6766 - 6775]
Pages: 10
DOI: 10.2174/0929867325666180705145900
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