SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects

Research output: Contribution to journalArticlepeer-review

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SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects. / Fletcher, Sarah J; Johnson, Ben; Lowe, Gillian C; Bem, Danai; Drake, Sian; Lordkipanidzé, Marie; Guiú, Isabel Sánchez; Dawood, Ban; Rivera, José; Simpson, Michael A; Daly, Martina E; Motwani, Jayashree; Collins, Peter W; Watson, Steve P; Morgan, Neil V; UK Genotyping and Phenotyping of Platelets study group.

In: Journal of Clinical Investigation, Vol. 125, No. 9, 01.09.2015, p. 3600-3605.

Research output: Contribution to journalArticlepeer-review

Harvard

Fletcher, SJ, Johnson, B, Lowe, GC, Bem, D, Drake, S, Lordkipanidzé, M, Guiú, IS, Dawood, B, Rivera, J, Simpson, MA, Daly, ME, Motwani, J, Collins, PW, Watson, SP, Morgan, NV & UK Genotyping and Phenotyping of Platelets study group 2015, 'SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects', Journal of Clinical Investigation, vol. 125, no. 9, pp. 3600-3605. https://doi.org/10.1172/JCI80347

APA

Fletcher, S. J., Johnson, B., Lowe, G. C., Bem, D., Drake, S., Lordkipanidzé, M., Guiú, I. S., Dawood, B., Rivera, J., Simpson, M. A., Daly, M. E., Motwani, J., Collins, P. W., Watson, S. P., Morgan, N. V., & UK Genotyping and Phenotyping of Platelets study group (2015). SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects. Journal of Clinical Investigation, 125(9), 3600-3605. https://doi.org/10.1172/JCI80347

Vancouver

Author

Fletcher, Sarah J ; Johnson, Ben ; Lowe, Gillian C ; Bem, Danai ; Drake, Sian ; Lordkipanidzé, Marie ; Guiú, Isabel Sánchez ; Dawood, Ban ; Rivera, José ; Simpson, Michael A ; Daly, Martina E ; Motwani, Jayashree ; Collins, Peter W ; Watson, Steve P ; Morgan, Neil V ; UK Genotyping and Phenotyping of Platelets study group. / SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 9. pp. 3600-3605.

Bibtex

@article{ac3414b85c064018b9cd780e755cedd4,
title = "SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects",
abstract = "Inherited thrombocytopenias are a group of disorders that are characterized by a low platelet count and are sometimes associated with excessive bleeding that ranges from mild to severe. We evaluated 36 unrelated patients and 17 family members displaying thrombocytopenia that were recruited to the UK Genotyping and Phenotyping of Platelets (GAPP) study. All patients had a history of excessive bleeding of unknown etiology. We performed platelet phenotyping and whole-exome sequencing (WES) on all patients and identified mutations in schlafen 14 (SLFN14) in 12 patients from 3 unrelated families. Patients harboring SLFN14 mutations displayed an analogous phenotype that consisted of moderate thrombocytopenia, enlarged platelets, decreased ATP secretion, and a dominant inheritance pattern. Three heterozygous missense mutations were identified in affected family members and predicted to encode substitutions (K218E, K219N, and V220D) within an ATPase-AAA-4, GTP/ATP-binding region of SLFN14. Endogenous SLFN14 expression was reduced in platelets from all patients, and mutant SLFN14 expression was markedly decreased compared with that of WT SLFN14 when overexpressed in transfected cells. Electron microscopy revealed a reduced number of dense granules in affected patients platelets, correlating with a decreased ATP secretion observed in lumiaggregometry studies. These results identify SLFN14 mutations as cause for an inherited thrombocytopenia with excessive bleeding, outlining a fundamental role for SLFN14 in platelet formation and function.",
author = "Fletcher, {Sarah J} and Ben Johnson and Lowe, {Gillian C} and Danai Bem and Sian Drake and Marie Lordkipanidz{\'e} and Gui{\'u}, {Isabel S{\'a}nchez} and Ban Dawood and Jos{\'e} Rivera and Simpson, {Michael A} and Daly, {Martina E} and Jayashree Motwani and Collins, {Peter W} and Watson, {Steve P} and Morgan, {Neil V} and {UK Genotyping and Phenotyping of Platelets study group}",
year = "2015",
month = sep,
day = "1",
doi = "10.1172/JCI80347",
language = "English",
volume = "125",
pages = "3600--3605",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "American Society for Clinical Investigation",
number = "9",

}

RIS

TY - JOUR

T1 - SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects

AU - Fletcher, Sarah J

AU - Johnson, Ben

AU - Lowe, Gillian C

AU - Bem, Danai

AU - Drake, Sian

AU - Lordkipanidzé, Marie

AU - Guiú, Isabel Sánchez

AU - Dawood, Ban

AU - Rivera, José

AU - Simpson, Michael A

AU - Daly, Martina E

AU - Motwani, Jayashree

AU - Collins, Peter W

AU - Watson, Steve P

AU - Morgan, Neil V

AU - UK Genotyping and Phenotyping of Platelets study group

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Inherited thrombocytopenias are a group of disorders that are characterized by a low platelet count and are sometimes associated with excessive bleeding that ranges from mild to severe. We evaluated 36 unrelated patients and 17 family members displaying thrombocytopenia that were recruited to the UK Genotyping and Phenotyping of Platelets (GAPP) study. All patients had a history of excessive bleeding of unknown etiology. We performed platelet phenotyping and whole-exome sequencing (WES) on all patients and identified mutations in schlafen 14 (SLFN14) in 12 patients from 3 unrelated families. Patients harboring SLFN14 mutations displayed an analogous phenotype that consisted of moderate thrombocytopenia, enlarged platelets, decreased ATP secretion, and a dominant inheritance pattern. Three heterozygous missense mutations were identified in affected family members and predicted to encode substitutions (K218E, K219N, and V220D) within an ATPase-AAA-4, GTP/ATP-binding region of SLFN14. Endogenous SLFN14 expression was reduced in platelets from all patients, and mutant SLFN14 expression was markedly decreased compared with that of WT SLFN14 when overexpressed in transfected cells. Electron microscopy revealed a reduced number of dense granules in affected patients platelets, correlating with a decreased ATP secretion observed in lumiaggregometry studies. These results identify SLFN14 mutations as cause for an inherited thrombocytopenia with excessive bleeding, outlining a fundamental role for SLFN14 in platelet formation and function.

AB - Inherited thrombocytopenias are a group of disorders that are characterized by a low platelet count and are sometimes associated with excessive bleeding that ranges from mild to severe. We evaluated 36 unrelated patients and 17 family members displaying thrombocytopenia that were recruited to the UK Genotyping and Phenotyping of Platelets (GAPP) study. All patients had a history of excessive bleeding of unknown etiology. We performed platelet phenotyping and whole-exome sequencing (WES) on all patients and identified mutations in schlafen 14 (SLFN14) in 12 patients from 3 unrelated families. Patients harboring SLFN14 mutations displayed an analogous phenotype that consisted of moderate thrombocytopenia, enlarged platelets, decreased ATP secretion, and a dominant inheritance pattern. Three heterozygous missense mutations were identified in affected family members and predicted to encode substitutions (K218E, K219N, and V220D) within an ATPase-AAA-4, GTP/ATP-binding region of SLFN14. Endogenous SLFN14 expression was reduced in platelets from all patients, and mutant SLFN14 expression was markedly decreased compared with that of WT SLFN14 when overexpressed in transfected cells. Electron microscopy revealed a reduced number of dense granules in affected patients platelets, correlating with a decreased ATP secretion observed in lumiaggregometry studies. These results identify SLFN14 mutations as cause for an inherited thrombocytopenia with excessive bleeding, outlining a fundamental role for SLFN14 in platelet formation and function.

U2 - 10.1172/JCI80347

DO - 10.1172/JCI80347

M3 - Article

C2 - 26280575

VL - 125

SP - 3600

EP - 3605

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 9

ER -