Cargando…

A Novel Role for CSRP1 in a Lebanese Family with Congenital Cardiac Defects

Despite an obvious role for consanguinity in congenital heart disease (CHD), most studies fail to document a monogenic model of inheritance except for few cases. We hereby describe a first-degree cousins consanguineous Lebanese family with 7 conceived children: 2 died in utero of unknown causes, 3 h...

Descripción completa

Detalles Bibliográficos
Autores principales: Kamar, Amina, Fahed, Akl C., Shibbani, Kamel, El-Hachem, Nehme, Bou-Slaiman, Salim, Arabi, Mariam, Kurban, Mazen, Seidman, Jonathan G., Seidman, Christine E., Haidar, Rachid, Baydoun, Elias, Nemer, Georges, Bitar, Fadi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741687/
https://www.ncbi.nlm.nih.gov/pubmed/29326753
http://dx.doi.org/10.3389/fgene.2017.00217
_version_ 1783288227699884032
author Kamar, Amina
Fahed, Akl C.
Shibbani, Kamel
El-Hachem, Nehme
Bou-Slaiman, Salim
Arabi, Mariam
Kurban, Mazen
Seidman, Jonathan G.
Seidman, Christine E.
Haidar, Rachid
Baydoun, Elias
Nemer, Georges
Bitar, Fadi
author_facet Kamar, Amina
Fahed, Akl C.
Shibbani, Kamel
El-Hachem, Nehme
Bou-Slaiman, Salim
Arabi, Mariam
Kurban, Mazen
Seidman, Jonathan G.
Seidman, Christine E.
Haidar, Rachid
Baydoun, Elias
Nemer, Georges
Bitar, Fadi
author_sort Kamar, Amina
collection PubMed
description Despite an obvious role for consanguinity in congenital heart disease (CHD), most studies fail to document a monogenic model of inheritance except for few cases. We hereby describe a first-degree cousins consanguineous Lebanese family with 7 conceived children: 2 died in utero of unknown causes, 3 have CHD, and 4 have polydactyly. The aim of the study is to unveil the genetic variant(s) causing these phenotypes using next generation sequencing (NGS) technology. Targeted exome sequencing identified a heterozygous duplication in CSRP1 which leads to a potential frameshift mutation at position 154 of the protein. This mutation is inherited from the father, and segregates only with the CHD phenotype. The in vitro characterization demonstrates that the mutation dramatically abrogates its transcriptional activity over cardiac promoters like NPPA. In addition, it differentially inhibits the physical association of CSRP1 with SRF, GATA4, and with the newly described partner herein TBX5. Whole exome sequencing failed to show any potential variant linked to polydactyly, but revealed a novel missense mutation in TRPS1. This mutation is inherited from the healthy mother, and segregating only with the cardiac phenotype. Both TRPS1 and CSRP1 physically interact, and the mutations in each abrogate their partnership. Our findings add fundamental knowledge into the molecular basis of CHD, and propose the di-genic model of inheritance as responsible for such malformations.
format Online
Article
Text
id pubmed-5741687
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-57416872018-01-11 A Novel Role for CSRP1 in a Lebanese Family with Congenital Cardiac Defects Kamar, Amina Fahed, Akl C. Shibbani, Kamel El-Hachem, Nehme Bou-Slaiman, Salim Arabi, Mariam Kurban, Mazen Seidman, Jonathan G. Seidman, Christine E. Haidar, Rachid Baydoun, Elias Nemer, Georges Bitar, Fadi Front Genet Genetics Despite an obvious role for consanguinity in congenital heart disease (CHD), most studies fail to document a monogenic model of inheritance except for few cases. We hereby describe a first-degree cousins consanguineous Lebanese family with 7 conceived children: 2 died in utero of unknown causes, 3 have CHD, and 4 have polydactyly. The aim of the study is to unveil the genetic variant(s) causing these phenotypes using next generation sequencing (NGS) technology. Targeted exome sequencing identified a heterozygous duplication in CSRP1 which leads to a potential frameshift mutation at position 154 of the protein. This mutation is inherited from the father, and segregates only with the CHD phenotype. The in vitro characterization demonstrates that the mutation dramatically abrogates its transcriptional activity over cardiac promoters like NPPA. In addition, it differentially inhibits the physical association of CSRP1 with SRF, GATA4, and with the newly described partner herein TBX5. Whole exome sequencing failed to show any potential variant linked to polydactyly, but revealed a novel missense mutation in TRPS1. This mutation is inherited from the healthy mother, and segregating only with the cardiac phenotype. Both TRPS1 and CSRP1 physically interact, and the mutations in each abrogate their partnership. Our findings add fundamental knowledge into the molecular basis of CHD, and propose the di-genic model of inheritance as responsible for such malformations. Frontiers Media S.A. 2017-12-18 /pmc/articles/PMC5741687/ /pubmed/29326753 http://dx.doi.org/10.3389/fgene.2017.00217 Text en Copyright © 2017 Kamar, Fahed, Shibbani, El-Hachem, Bou-Slaiman, Arabi, Kurban, Seidman, Seidman, Haidar, Baydoun, Nemer and Bitar. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Kamar, Amina
Fahed, Akl C.
Shibbani, Kamel
El-Hachem, Nehme
Bou-Slaiman, Salim
Arabi, Mariam
Kurban, Mazen
Seidman, Jonathan G.
Seidman, Christine E.
Haidar, Rachid
Baydoun, Elias
Nemer, Georges
Bitar, Fadi
A Novel Role for CSRP1 in a Lebanese Family with Congenital Cardiac Defects
title A Novel Role for CSRP1 in a Lebanese Family with Congenital Cardiac Defects
title_full A Novel Role for CSRP1 in a Lebanese Family with Congenital Cardiac Defects
title_fullStr A Novel Role for CSRP1 in a Lebanese Family with Congenital Cardiac Defects
title_full_unstemmed A Novel Role for CSRP1 in a Lebanese Family with Congenital Cardiac Defects
title_short A Novel Role for CSRP1 in a Lebanese Family with Congenital Cardiac Defects
title_sort novel role for csrp1 in a lebanese family with congenital cardiac defects
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741687/
https://www.ncbi.nlm.nih.gov/pubmed/29326753
http://dx.doi.org/10.3389/fgene.2017.00217
work_keys_str_mv AT kamaramina anovelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT fahedaklc anovelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT shibbanikamel anovelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT elhachemnehme anovelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT bouslaimansalim anovelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT arabimariam anovelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT kurbanmazen anovelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT seidmanjonathang anovelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT seidmanchristinee anovelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT haidarrachid anovelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT baydounelias anovelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT nemergeorges anovelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT bitarfadi anovelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT kamaramina novelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT fahedaklc novelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT shibbanikamel novelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT elhachemnehme novelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT bouslaimansalim novelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT arabimariam novelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT kurbanmazen novelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT seidmanjonathang novelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT seidmanchristinee novelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT haidarrachid novelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT baydounelias novelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT nemergeorges novelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects
AT bitarfadi novelroleforcsrp1inalebanesefamilywithcongenitalcardiacdefects