Remediation of ABCG5-Linked Macrothrombocytopenia With Ezetimibe Therapy
To investigate refractory hypercholesterolemia, a female patient and relatives were subjected to whole-genome sequencing. The proband was found to have compound heterozygous substitutions p. Arg446Gln and c.1118+3G>T in ABCG5, one of two genes causing sitosterolemia. When tracing these varian...
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2021
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oai:doaj.org-article:232adf64774b457ea2656e6350a4991e2021-11-22T04:43:17ZRemediation of ABCG5-Linked Macrothrombocytopenia With Ezetimibe Therapy1664-802110.3389/fgene.2021.769699https://doaj.org/article/232adf64774b457ea2656e6350a4991e2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fgene.2021.769699/fullhttps://doaj.org/toc/1664-8021To investigate refractory hypercholesterolemia, a female patient and relatives were subjected to whole-genome sequencing. The proband was found to have compound heterozygous substitutions p. Arg446Gln and c.1118+3G>T in ABCG5, one of two genes causing sitosterolemia. When tracing these variants in the full pedigree, all maternally related heterozygotes for the intronic ABCG5 variant exhibited large platelets (over 30 fl), which segregated in an autosomal dominant manner, consistent with macrothrombocytopenia, or large platelet syndrome which may be associated with a bleeding tendency. In vitro cell-line and in vivo rat model experiments supported a pathogenic role for the variant and the macrothrombocytopenia was recapitulated in heterozygous rats and human cell lines exhibiting that single variant. Ezetimibe treatment successfully ameliorated all the symptoms of the proband with sitosterolemia and resolved the macrothrombocytopenia of the treated heterozygote relatives. Subsequently, in follow up these observations, platelet size, and size distribution were measured in 1,180 individuals; 30 were found to be clinically abnormal, three of which carried a single known pathogenic ABCG5 variant (p.Arg446Ter) and two individuals carried novel ABCG5 variants of uncertain significance. In this study, we discovered that identification of large platelets and therefore a possible macrothrombocytopenia diagnosis could easily be inadvertently missed in clinical practice due to variable instrument settings. These findings suggest that ABCG5 heterozygosity may cause macrothrombocytopenia, that Ezetimibe treatment may resolve macrothrombocytopenia in such individuals, and that increased attention to platelet size on complete blood counts can aid in the identification of candidates for ABCG5 genetic testing who might benefit from Ezetimibe treatment.Libin DengLibin DengLibin DengJingsong XuWei ChenShicheng GuoRobert D. SteinerQi ChenZhujun ChengYanmei XuBei YaoXiaoyan LiXiaozhong WangKeyu DengSteven J. SchrodiDake ZhangHongbo XinFrontiers Media S.A.articleplateletbloodsitosterolemiahypercholesterolemiaezetimibe (EZE)GeneticsQH426-470ENFrontiers in Genetics, Vol 12 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
platelet blood sitosterolemia hypercholesterolemia ezetimibe (EZE) Genetics QH426-470 |
| spellingShingle |
platelet blood sitosterolemia hypercholesterolemia ezetimibe (EZE) Genetics QH426-470 Libin Deng Libin Deng Libin Deng Jingsong Xu Wei Chen Shicheng Guo Robert D. Steiner Qi Chen Zhujun Cheng Yanmei Xu Bei Yao Xiaoyan Li Xiaozhong Wang Keyu Deng Steven J. Schrodi Dake Zhang Hongbo Xin Remediation of ABCG5-Linked Macrothrombocytopenia With Ezetimibe Therapy |
| description |
To investigate refractory hypercholesterolemia, a female patient and relatives were subjected to whole-genome sequencing. The proband was found to have compound heterozygous substitutions p. Arg446Gln and c.1118+3G>T in ABCG5, one of two genes causing sitosterolemia. When tracing these variants in the full pedigree, all maternally related heterozygotes for the intronic ABCG5 variant exhibited large platelets (over 30 fl), which segregated in an autosomal dominant manner, consistent with macrothrombocytopenia, or large platelet syndrome which may be associated with a bleeding tendency. In vitro cell-line and in vivo rat model experiments supported a pathogenic role for the variant and the macrothrombocytopenia was recapitulated in heterozygous rats and human cell lines exhibiting that single variant. Ezetimibe treatment successfully ameliorated all the symptoms of the proband with sitosterolemia and resolved the macrothrombocytopenia of the treated heterozygote relatives. Subsequently, in follow up these observations, platelet size, and size distribution were measured in 1,180 individuals; 30 were found to be clinically abnormal, three of which carried a single known pathogenic ABCG5 variant (p.Arg446Ter) and two individuals carried novel ABCG5 variants of uncertain significance. In this study, we discovered that identification of large platelets and therefore a possible macrothrombocytopenia diagnosis could easily be inadvertently missed in clinical practice due to variable instrument settings. These findings suggest that ABCG5 heterozygosity may cause macrothrombocytopenia, that Ezetimibe treatment may resolve macrothrombocytopenia in such individuals, and that increased attention to platelet size on complete blood counts can aid in the identification of candidates for ABCG5 genetic testing who might benefit from Ezetimibe treatment. |
| format |
article |
| author |
Libin Deng Libin Deng Libin Deng Jingsong Xu Wei Chen Shicheng Guo Robert D. Steiner Qi Chen Zhujun Cheng Yanmei Xu Bei Yao Xiaoyan Li Xiaozhong Wang Keyu Deng Steven J. Schrodi Dake Zhang Hongbo Xin |
| author_facet |
Libin Deng Libin Deng Libin Deng Jingsong Xu Wei Chen Shicheng Guo Robert D. Steiner Qi Chen Zhujun Cheng Yanmei Xu Bei Yao Xiaoyan Li Xiaozhong Wang Keyu Deng Steven J. Schrodi Dake Zhang Hongbo Xin |
| author_sort |
Libin Deng |
| title |
Remediation of ABCG5-Linked Macrothrombocytopenia With Ezetimibe Therapy |
| title_short |
Remediation of ABCG5-Linked Macrothrombocytopenia With Ezetimibe Therapy |
| title_full |
Remediation of ABCG5-Linked Macrothrombocytopenia With Ezetimibe Therapy |
| title_fullStr |
Remediation of ABCG5-Linked Macrothrombocytopenia With Ezetimibe Therapy |
| title_full_unstemmed |
Remediation of ABCG5-Linked Macrothrombocytopenia With Ezetimibe Therapy |
| title_sort |
remediation of abcg5-linked macrothrombocytopenia with ezetimibe therapy |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/232adf64774b457ea2656e6350a4991e |
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