Germline mutations in the transcription factor IKZF5 cause thrombocytopenia
© 2019 by The American Society of Hematology..
To identify novel causes of hereditary thrombocytopenia, we performed a genetic association analysis of whole-genome sequencing data from 13 037 individuals enrolled in the National Institute for Health Research (NIHR) BioResource, including 233 cases with isolated thrombocytopenia. We found an association between rare variants in the transcription factor-encoding gene IKZF5 and thrombocytopenia. We report 5 causal missense variants in or near IKZF5 zinc fingers, of which 2 occurred de novo and 3 co-segregated in 3 pedigrees. A canonical DNA-zinc finger binding model predicts that 3 of the variants alter DNA recognition. Expression studies showed that chromatin binding was disrupted in mutant compared with wild-type IKZF5, and electron microscopy revealed a reduced quantity of α granules in normally sized platelets. Proplatelet formation was reduced in megakaryocytes from 7 cases relative to 6 controls. Comparison of RNA-sequencing data from platelets, monocytes, neutrophils, and CD4+ T cells from 3 cases and 14 healthy controls showed 1194 differentially expressed genes in platelets but only 4 differentially expressed genes in each of the other blood cell types. In conclusion, IKZF5 is a novel transcriptional regulator of megakaryopoiesis and the eighth transcription factor associated with dominant thrombocytopenia in humans.
| Errataetall: |
CommentIn: Blood. 2019 Dec 5;134(23):2000-2002. - PMID 31805194 |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2019 |
|---|---|
| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:134 |
|---|---|
| Enthalten in: |
Blood - 134(2019), 23 vom: 05. Dez., Seite 2070-2081 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Lentaigne, Claire [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
148971-36-2 |
|---|
| Anmerkungen: |
Date Completed 17.03.2020 Date Revised 02.02.2021 published: Print CommentIn: Blood. 2019 Dec 5;134(23):2000-2002. - PMID 31805194 Citation Status MEDLINE |
|---|
| doi: |
10.1182/blood.2019000782 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM298333678 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM298333678 | ||
| 003 | DE-627 | ||
| 005 | 20231225093929.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2019 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1182/blood.2019000782 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0994.xml |
| 035 | |a (DE-627)NLM298333678 | ||
| 035 | |a (NLM)31217188 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Lentaigne, Claire |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Germline mutations in the transcription factor IKZF5 cause thrombocytopenia |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 17.03.2020 | ||
| 500 | |a Date Revised 02.02.2021 | ||
| 500 | |a published: Print | ||
| 500 | |a CommentIn: Blood. 2019 Dec 5;134(23):2000-2002. - PMID 31805194 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2019 by The American Society of Hematology. | ||
| 520 | |a To identify novel causes of hereditary thrombocytopenia, we performed a genetic association analysis of whole-genome sequencing data from 13 037 individuals enrolled in the National Institute for Health Research (NIHR) BioResource, including 233 cases with isolated thrombocytopenia. We found an association between rare variants in the transcription factor-encoding gene IKZF5 and thrombocytopenia. We report 5 causal missense variants in or near IKZF5 zinc fingers, of which 2 occurred de novo and 3 co-segregated in 3 pedigrees. A canonical DNA-zinc finger binding model predicts that 3 of the variants alter DNA recognition. Expression studies showed that chromatin binding was disrupted in mutant compared with wild-type IKZF5, and electron microscopy revealed a reduced quantity of α granules in normally sized platelets. Proplatelet formation was reduced in megakaryocytes from 7 cases relative to 6 controls. Comparison of RNA-sequencing data from platelets, monocytes, neutrophils, and CD4+ T cells from 3 cases and 14 healthy controls showed 1194 differentially expressed genes in platelets but only 4 differentially expressed genes in each of the other blood cell types. In conclusion, IKZF5 is a novel transcriptional regulator of megakaryopoiesis and the eighth transcription factor associated with dominant thrombocytopenia in humans | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Chromatin |2 NLM | |
| 650 | 7 | |a IKZF5 protein, human |2 NLM | |
| 650 | 7 | |a Ikaros Transcription Factor |2 NLM | |
| 650 | 7 | |a 148971-36-2 |2 NLM | |
| 700 | 1 | |a Greene, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Sivapalaratnam, Suthesh |e verfasserin |4 aut | |
| 700 | 1 | |a Favier, Remi |e verfasserin |4 aut | |
| 700 | 1 | |a Seyres, Denis |e verfasserin |4 aut | |
| 700 | 1 | |a Thys, Chantal |e verfasserin |4 aut | |
| 700 | 1 | |a Grassi, Luigi |e verfasserin |4 aut | |
| 700 | 1 | |a Mangles, Sarah |e verfasserin |4 aut | |
| 700 | 1 | |a Sibson, Keith |e verfasserin |4 aut | |
| 700 | 1 | |a Stubbs, Matthew |e verfasserin |4 aut | |
| 700 | 1 | |a Burden, Frances |e verfasserin |4 aut | |
| 700 | 1 | |a Bordet, Jean-Claude |e verfasserin |4 aut | |
| 700 | 1 | |a Armari-Alla, Corinne |e verfasserin |4 aut | |
| 700 | 1 | |a Erber, Wendy |e verfasserin |4 aut | |
| 700 | 1 | |a Farrow, Samantha |e verfasserin |4 aut | |
| 700 | 1 | |a Gleadall, Nicholas |e verfasserin |4 aut | |
| 700 | 1 | |a Gomez, Keith |e verfasserin |4 aut | |
| 700 | 1 | |a Megy, Karyn |e verfasserin |4 aut | |
| 700 | 1 | |a Papadia, Sofia |e verfasserin |4 aut | |
| 700 | 1 | |a Penkett, Christopher J |e verfasserin |4 aut | |
| 700 | 1 | |a Sims, Matthew C |e verfasserin |4 aut | |
| 700 | 1 | |a Stefanucci, Luca |e verfasserin |4 aut | |
| 700 | 1 | |a Stephens, Jonathan C |e verfasserin |4 aut | |
| 700 | 1 | |a Read, Randy J |e verfasserin |4 aut | |
| 700 | 1 | |a Stirrups, Kathleen E |e verfasserin |4 aut | |
| 700 | 1 | |a Ouwehand, Willem H |e verfasserin |4 aut | |
| 700 | 1 | |a Laffan, Michael A |e verfasserin |4 aut | |
| 700 | 0 | |a NIHR BioResource |e verfasserin |4 aut | |
| 700 | 1 | |a Frontini, Mattia |e verfasserin |4 aut | |
| 700 | 1 | |a Freson, Kathleen |e verfasserin |4 aut | |
| 700 | 1 | |a Turro, Ernest |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Blood |d 1946 |g 134(2019), 23 vom: 05. Dez., Seite 2070-2081 |w (DE-627)NLM000014761 |x 1528-0020 |7 nnns |
| 773 | 1 | 8 | |g volume:134 |g year:2019 |g number:23 |g day:05 |g month:12 |g pages:2070-2081 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1182/blood.2019000782 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 134 |j 2019 |e 23 |b 05 |c 12 |h 2070-2081 | ||