Michalk, Anne and Stricker, Sigmar and Becker, Jutta and Rupps, Rosemarie and Pantzar, Tapio and Miertus, Jan and Botta, Giovanni and Naretto, Valeria G. and Janetzki, Catrin and Yaqoob, Nausheen and Ott, Claus-Eric and Seelow, Dominik and Wieczorek, Dagmar and Fiebig, Britta and Wirth, Brunhilde and Hoopmann, Markus and Walther, Marisa and Koerber, Friederike and Blankenburg, Markus and Mundlos, Stefan and Heller, Raoul and Hoffmann, Katrin (2008) Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. AMERICAN JOURNAL OF HUMAN GENETICS, 82 (2). pp. 464-476. ISSN 0002-9297, 1537-6605
Full text not available from this repository. (Request a copy)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 gamma subunit (CHRNG) of AChR were found in two FADS disorders, lethal multiple pterygium syndrome (LMPS) and Escobar syndrome. Other AChR subunits alpha 1, beta 1, and delta (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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ARTHROGRYPOSIS MULTIPLEX CONGENITA; NEUROMUSCULAR-JUNCTION SYNAPTOPATHY; DELTA-SUBUNIT MUTATION; MYASTHENIC SYNDROME; PTERYGIUM SYNDROME; RAPSYN MUTATIONS; BINDING; LETHAL; UNDERLIE; ORIGIN; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Humangenetik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 09 Nov 2020 12:22 |
| Last Modified: | 09 Nov 2020 12:22 |
| URI: | https://pred.uni-regensburg.de/id/eprint/31384 |
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