title: Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders.
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.
authors.affiliation: Institute for Medical Genetics, Charité University Medicine, Augustenburger Platz 1, D-13353 Berlin, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Michalk
authors.forename: Sigmar
authors.initials: S
authors.lastname: Stricker
authors.forename: Jutta
authors.initials: J
authors.lastname: Becker
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Rupps
authors.forename: Tapio
authors.initials: T
authors.lastname: Pantzar
authors.forename: Jan
authors.initials: J
authors.lastname: Miertus
authors.forename: Giovanni
authors.initials: G
authors.lastname: Botta
authors.forename: Valeria G
authors.initials: VG
authors.lastname: Naretto
authors.forename: Catrin
authors.initials: C
authors.lastname: Janetzki
authors.forename: Nausheen
authors.initials: N
authors.lastname: Yaqoob
authors.forename: Claus-Eric
authors.initials: CE
authors.lastname: Ott
authors.forename: Dominik
authors.initials: D
authors.lastname: Seelow
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.forename: Britta
authors.initials: B
authors.lastname: Fiebig
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Wirth
authors.forename: Markus
authors.initials: M
authors.lastname: Hoopmann
authors.forename: Marisa
authors.initials: M
authors.lastname: Walther
authors.forename: Friederike
authors.initials: F
authors.lastname: Körber
authors.forename: Markus
authors.initials: M
authors.lastname: Blankenburg
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.forename: Raoul
authors.initials: R
authors.lastname: Heller
authors.forename: Katrin
authors.initials: K
authors.lastname: Hoffmann
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D005315:Fetal Diseases / Q000235:genetics*; D005808:Genes, Recessive / Q000235:genetics; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D020294:Myasthenic Syndromes, Congenital / Q000196:embryology / Q000235:genetics*; D010375:Pedigree; D011950:Receptors, Cholinergic / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics*
chemical_list: C523021:CHRNA1 protein, human; C514767:CHRND protein, human; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic