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  Escobar Syndrome Is a Prenatal Myasthenia Caused by Disruption of the Acetylcholine Receptor Fetal γ Subunit

Hoffmann, K., Müller, J. S., Stricker, S., Megarbane, A., Rajab, A., Lindner, T. H., et al. (2006). Escobar Syndrome Is a Prenatal Myasthenia Caused by Disruption of the Acetylcholine Receptor Fetal γ Subunit. American Journal of Human Genetics (Chicago, IL), 79(2), 303-312.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-83D9-D Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-83DA-B
Genre: Journal Article
Alternative Title : Am J Hum Genet

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 Creators:
Hoffmann, Katrin1, Author              
Müller, Juliane S., Author
Stricker, Sigmar1, Author              
Megarbane, Andre, Author
Rajab, Anna, Author
Lindner, Tom H., Author
Cohen, Monika, Author
Chouery, Eliane, Author
Adaimy, Lynn, Author
Ghanem, Ismat, Author
Delague, Valerie, Author
Boltshauser, Eugen, Author
Talim, Beril, Author
Horvath, Rita, Author
Robinson, Peter N.1, Author              
Lochmüller, Hanns, Author
Hübner, Christoph, Author
Mundlos, Stefan1, Author              
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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 Abstract: 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 myasthenic 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.

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Language(s): eng - English
 Dates: 2006-08
 Publication Status: Published in print
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 Rev. Type: -
 Identifiers: eDoc: 313086
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Title: American Journal of Human Genetics (Chicago, IL)
  Alternative Title : Am J Hum Genet
Source Genre: Journal
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Publ. Info: -
Pages: - Volume / Issue: 79 (2) Sequence Number: - Start / End Page: 303 - 312 Identifier: ISSN: 0002-9297