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Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes
PURPOSE: Several clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly or capillary malformations with arteriovenous malformations 2 (CM-AVM2) have been associated with EPHB4 (Ephrin type B receptor 4) variants, demanding new approaches for deciphering pathogenesis of nov...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group US
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257501/ https://www.ncbi.nlm.nih.gov/pubmed/33864021 http://dx.doi.org/10.1038/s41436-021-01136-7 |
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author | Martin-Almedina, Silvia Ogmen, Kazim Sackey, Ege Grigoriadis, Dionysios Karapouliou, Christina Nadarajah, Noeline Ebbing, Cathrine Lord, Jenny Mellis, Rhiannon Kortuem, Fanny Dinulos, Mary Beth Polun, Cassandra Bale, Sherri Atton, Giles Robinson, Alexandra Reigstad, Hallvard Houge, Gunnar von der Wense, Axel Becker, Wolf-Henning Jeffery, Steve Mortimer, Peter S. Gordon, Kristiana Josephs, Katherine S. Robart, Sarah Kilby, Mark D. Vallee, Stephanie Gorski, Jerome L. Hempel, Maja Berland, Siren Mansour, Sahar Ostergaard, Pia |
author_facet | Martin-Almedina, Silvia Ogmen, Kazim Sackey, Ege Grigoriadis, Dionysios Karapouliou, Christina Nadarajah, Noeline Ebbing, Cathrine Lord, Jenny Mellis, Rhiannon Kortuem, Fanny Dinulos, Mary Beth Polun, Cassandra Bale, Sherri Atton, Giles Robinson, Alexandra Reigstad, Hallvard Houge, Gunnar von der Wense, Axel Becker, Wolf-Henning Jeffery, Steve Mortimer, Peter S. Gordon, Kristiana Josephs, Katherine S. Robart, Sarah Kilby, Mark D. Vallee, Stephanie Gorski, Jerome L. Hempel, Maja Berland, Siren Mansour, Sahar Ostergaard, Pia |
author_sort | Martin-Almedina, Silvia |
collection | PubMed |
description | PURPOSE: Several clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly or capillary malformations with arteriovenous malformations 2 (CM-AVM2) have been associated with EPHB4 (Ephrin type B receptor 4) variants, demanding new approaches for deciphering pathogenesis of novel variants of uncertain significance (VUS) identified in EPHB4, and for the identification of differentiated disease mechanisms at the molecular level. METHODS: Ten index cases with various phenotypes, either fetal hydrops, CM-AVM2, or peripheral lower limb lymphedema, whose distinct clinical phenotypes are described in detail in this study, presented with a variant in EPHB4. In vitro functional studies were performed to confirm pathogenicity. RESULTS: Pathogenicity was demonstrated for six of the seven novel EPHB4 VUS investigated. A heterogeneity of molecular disease mechanisms was identified, from loss of protein production or aberrant subcellular localization to total reduction of the phosphorylation capability of the receptor. There was some phenotype–genotype correlation; however, previously unreported intrafamilial overlapping phenotypes such as lymphatic-related fetal hydrops (LRFH) and CM-AVM2 in the same family were observed. CONCLUSION: This study highlights the usefulness of protein expression and subcellular localization studies to predict EPHB4 variant pathogenesis. Our accurate clinical phenotyping expands our interpretation of the Janus-faced spectrum of EPHB4-related disorders, introducing the discovery of cases with overlapping phenotypes. |
format | Online Article Text |
id | pubmed-8257501 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
spelling | pubmed-82575012021-07-23 Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes Martin-Almedina, Silvia Ogmen, Kazim Sackey, Ege Grigoriadis, Dionysios Karapouliou, Christina Nadarajah, Noeline Ebbing, Cathrine Lord, Jenny Mellis, Rhiannon Kortuem, Fanny Dinulos, Mary Beth Polun, Cassandra Bale, Sherri Atton, Giles Robinson, Alexandra Reigstad, Hallvard Houge, Gunnar von der Wense, Axel Becker, Wolf-Henning Jeffery, Steve Mortimer, Peter S. Gordon, Kristiana Josephs, Katherine S. Robart, Sarah Kilby, Mark D. Vallee, Stephanie Gorski, Jerome L. Hempel, Maja Berland, Siren Mansour, Sahar Ostergaard, Pia Genet Med Article PURPOSE: Several clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly or capillary malformations with arteriovenous malformations 2 (CM-AVM2) have been associated with EPHB4 (Ephrin type B receptor 4) variants, demanding new approaches for deciphering pathogenesis of novel variants of uncertain significance (VUS) identified in EPHB4, and for the identification of differentiated disease mechanisms at the molecular level. METHODS: Ten index cases with various phenotypes, either fetal hydrops, CM-AVM2, or peripheral lower limb lymphedema, whose distinct clinical phenotypes are described in detail in this study, presented with a variant in EPHB4. In vitro functional studies were performed to confirm pathogenicity. RESULTS: Pathogenicity was demonstrated for six of the seven novel EPHB4 VUS investigated. A heterogeneity of molecular disease mechanisms was identified, from loss of protein production or aberrant subcellular localization to total reduction of the phosphorylation capability of the receptor. There was some phenotype–genotype correlation; however, previously unreported intrafamilial overlapping phenotypes such as lymphatic-related fetal hydrops (LRFH) and CM-AVM2 in the same family were observed. CONCLUSION: This study highlights the usefulness of protein expression and subcellular localization studies to predict EPHB4 variant pathogenesis. Our accurate clinical phenotyping expands our interpretation of the Janus-faced spectrum of EPHB4-related disorders, introducing the discovery of cases with overlapping phenotypes. Nature Publishing Group US 2021-04-16 2021 /pmc/articles/PMC8257501/ /pubmed/33864021 http://dx.doi.org/10.1038/s41436-021-01136-7 Text en © The Author(s) 2021, corrected publication 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Martin-Almedina, Silvia Ogmen, Kazim Sackey, Ege Grigoriadis, Dionysios Karapouliou, Christina Nadarajah, Noeline Ebbing, Cathrine Lord, Jenny Mellis, Rhiannon Kortuem, Fanny Dinulos, Mary Beth Polun, Cassandra Bale, Sherri Atton, Giles Robinson, Alexandra Reigstad, Hallvard Houge, Gunnar von der Wense, Axel Becker, Wolf-Henning Jeffery, Steve Mortimer, Peter S. Gordon, Kristiana Josephs, Katherine S. Robart, Sarah Kilby, Mark D. Vallee, Stephanie Gorski, Jerome L. Hempel, Maja Berland, Siren Mansour, Sahar Ostergaard, Pia Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes |
title | Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes |
title_full | Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes |
title_fullStr | Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes |
title_full_unstemmed | Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes |
title_short | Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes |
title_sort | janus-faced ephb4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257501/ https://www.ncbi.nlm.nih.gov/pubmed/33864021 http://dx.doi.org/10.1038/s41436-021-01136-7 |
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