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Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders |
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| Authors: | Michalk Anne Stricker Sigmar Becker Jutta Rupps Rosemarie Pantzar Tapio Miertus Jan Botta Giovanni Naretto Valeria G Janetzki Catrin Yaqoob Nausheen Ott Claus-Eric Seelow Dominik Wieczorek Dagmar Fiebig Britta Wirth Brunhilde Hoopmann Markus Walther Marisa Körber Friederike Blankenburg Markus Mundlos Stefan Heller Raoul Hoffmann Katrin |
| Affiliation: | 1 Institute for Medical Genetics, Charité University Medicine, Augustenburger Platz 1, D-13353 Berlin, Germany 2 FG Development & Disease, Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, D-14195 Berlin, Germany 3 Institute of Human Genetics, University of Cologne, Kerpener Str. 34, D-50931 Cologne, Germany 4 Prenatal Medicine, Department of Gynaecology and Obstetrics, University of Cologne, Kerpener Str. 34, D-50931 Cologne, Germany 5 Departments of Medical Genetics and Pathology, BCCH Children's Hospital, Vancouver, BC V6H3V4, Canada 6 Medical Genetics Department, St. Elizabeth Cancer Institute, Heydukova 10, Bratislava 812 50, Slovakia 7 Department of Pathology, “OIRM-S.Anna” Hospital, Corso Spezia, 60, I-10126 Torino, Italy 8 Azienda Ospedaliera San Giovanni Battista di Torino, Via Santena 19, I-10126 Torino, Italy 9 Consultant Histopathologist, King Abdul Aziz Specialist Hospital, Taif, Saudi Arabia 10 Institute of Human Genetics, University of Duisburg-Essen, Campus Essen, Hufelandstr. 55, D-45122 Essen, Germany 11 Centre for Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93053 Regensburg, Germany 12 Institute of Genetics and Centre for Molecular Medicine, University of Cologne, Zülpicher Str. 47, D-50674 Cologne, Germany 13 Medical Centre of Rheumatology Berlin-Buch, Karower Str. 11, D-13125 Berlin, Germany 14 Department of Paediatric Radiology, University of Cologne, Joseph-Stelzmann-Strasse 9, D-50931 Cologne, Germany 15 Department of Neuropaediatrics, Vestische Kinder- und Jugendklinik, University of Witten/Herdecke, Dr.-Friedrich-Steiner Str. 5, D-45711 Datteln, Germany |
| 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 alpha1, beta1, 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. |
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