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  Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders

Michalk1, A., Stricker, S., Becker, J., Rupps, R., Pantzar, T., Miertus, J., et al. (2008). Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. The American Journal of Human Genetics, 82(2), 464-476. doi:10.1016/j.ajhg.2007.11.006.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-8064-B Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-8065-9
Genre: Journal Article
Alternative Title : Am J Hum Genet

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 Creators:
Michalk1, Anne, Author
Stricker, Sigmar1, Author              
Becker, Jutta, Author
Rupps, Rosemarie, Author
Pantzar, Tapio, Author
Miertus, Jan, Author
Botta, Giovanni, Author
Naretto, Valeria G., Author
Janetzki, Catrin, Author
Yaqoob, Nausheen, Author
Ott, Claus-Eric, Author
Seelow, Dominik1, Author              
Wieczorek, Dagmar, Author
Fiebig, Britta, Author
Wirth, Brunhilde, Author
Hoopmann, Markus, Author
Walther, Marisa, Author
Körber, Friederike, Author
Blankenburg, Markus, Author
Mundlos, Stefan1, Author              
Heller, Raoul, AuthorHoffmann, Katrin1, Author               more..
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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 Abstract: Impaired fetal movement causes malformations, summarized as fetal akinesia deformation sequence (FADS), and is triggered by environmental and genetic factors. Acetylcholine receptor (AChR) components are suspects because mutations in the fetally expressed subunit (CHRNG) of AChR were found in two FADS disorders, lethal multiple pterygium syndrome (LMPS) and Escobar syndrome. Other AChR subunits 1, 1, and (CHRNA1, CHRNB1, CHRND) as well as receptor-associated protein of the synapse (RAPSN) previously revealed missense or compound nonsense-missense mutations in viable congenital myasthenic syndrome; lethality of homozygous null mutations was predicted but never shown. We provide the first report to our knowledge of homozygous nonsense mutations in CHRNA1 and CHRND and show that they were lethal, whereas novel recessive missense mutations in RAPSN caused a severe but not necessarily lethal phenotype. To elucidate disease-associated malformations such as frequent abortions, fetal edema, cystic hygroma, or cardiac defects, we studied Chrna1, Chrnb1, Chrnd, Chrng, and Rapsn in mouse embryos and found expression in skeletal muscles but also in early somite development. This indicates that early developmental defects might be due to somite expression in addition to solely muscle-specific effects. We conclude that complete or severe functional disruption of fetal AChR causes lethal multiple pterygium syndrome whereas milder alterations result in fetal hypokinesia with inborn contractures or a myasthenic syndrome later in life.

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Title: The American Journal of Human Genetics,
  Alternative Title : Am J Hum Genet
Source Genre: Journal
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Affiliations:
Publ. Info: -
Pages: - Volume / Issue: 82 (2) Sequence Number: - Start / End Page: 464 - 476 Identifier: -