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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal γ subunit
American Journal of Human Genetics, Volume 79, No. 2, Year 2006
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Description
Escobar syndrome is a form of arthrogryposis multiplex congenita and features joint contractures, pterygia, and respiratory distress. Similar findings occur in newborns exposed to nicotinergic acetylcholine receptor (AChR) antibodies from myasthenie mothers. We performed linkage studies in families with Escobar syndrome and identified eight mutations within the γ-subunit gene (CHRNG) of the AChR. Our functional studies show that γ-subunit mutations prevent the correct localization of the fetal AChR in human embryonic kidney-cell membranes and that the expression pattern in prenatal mice corresponds to the human clinical phenotype. AChRs have five subunits. Two α, one β, and one δ subunit are always present. By switching γ to ε subunits in late fetal development, fetal AChRs are gradually replaced by adult AChRs. Fetal and adult AChRs are essential for neuromuscular signal transduction. In addition, the fetal AChRs seem to be the guide for the primary encounter of axon and muscle. Because of this important function in organogenesis, human mutations in the γ subunit were thought to be lethal, as they are in γ-knockout mice. In contrast, many mutations in other subunits have been found to be viable but cause postnatally persisting or beginning myasthenic syndromes. We conclude that Escobar syndrome is an inherited fetal myasthenic disease that also affects neuromuscular organogenesis. Because γ expression is restricted to early development, patients have no myasthenic symptoms later in life. This is the major difference from mutations in the other AChR subunits and the striking parallel to the symptoms found in neonates with arthrogryposis when maternal AChR auto-antibodies crossed the placenta and caused the transient inactivation of the AChR pathway. © 2006 by The American Society of Human Genetics. All rights reserved.
Authors & Co-Authors
Hoffmann, Katrin Katrin
Germany, Berlin
Humboldt-universität zu Berlin
Germany, Berlin
Charité – Universitätsmedizin Berlin
Müller, Juliane S.
Germany, Munich
Klinikum Der Universität München
Stricker, Sigmar
Germany, Berlin
Max Planck Institute for Molecular Genetics
Megarbane, Andre
Lebanon, Beirut
Université Saint-joseph de Beyrouth
Rajab, Anna A.
Oman, Muscat
Ministry of Health Oman
Lindner, Tom H.
Germany, Erlangen
Friedrich-alexander-universität Erlangen-nürnberg
Cohen, Monika
Germany, Munich
Kinderzentrum München
Chouery, Éliane
Lebanon, Beirut
Université Saint-joseph de Beyrouth
Adaimy, Lynn
Lebanon, Beirut
Université Saint-joseph de Beyrouth
Ghanem, Ismat B.
Lebanon, Beirut
Université Saint-joseph de Beyrouth
Delague, Valeŕie
Lebanon, Beirut
Université Saint-joseph de Beyrouth
Boltshauser, Eugen J.
Switzerland, Zurich
Kinderspital Zürich
Talim, Beril
Turkey, Ankara
Hacettepe Üniversitesi
Horvàth, Rita
Germany, Munich
Klinikum Schwabing
Robinson, Peter Nicholas
Germany, Berlin
Humboldt-universität zu Berlin
Lochmüller, Hanns
Germany, Munich
Klinikum Der Universität München
Hübner, Christoph
Germany, Berlin
Humboldt-universität zu Berlin
Mundlos, Stefan
Germany, Berlin
Humboldt-universität zu Berlin
Germany, Berlin
Max Planck Institute for Molecular Genetics
Statistics
Citations: 149
Authors: 18
Affiliations: 11
Identifiers
Doi:
10.1086/506257
ISSN:
00029297
Research Areas
Genetics And Genomics
Maternal And Child Health