Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders.
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.
Michalk
Anne
A
Institute for Medical Genetics, Charité University Medicine, Augustenburger Platz 1, D-13353 Berlin, Germany.
Stricker
Sigmar
S
Becker
Jutta
J
Rupps
Rosemarie
R
Pantzar
Tapio
T
Miertus
Jan
J
Botta
Giovanni
G
Naretto
Valeria G
VG
Janetzki
Catrin
C
Yaqoob
Nausheen
N
Ott
Claus-Eric
CE
Seelow
Dominik
D
Wieczorek
Dagmar
D
Fiebig
Britta
B
Wirth
Brunhilde
B
Hoopmann
Markus
M
Walther
Marisa
M
Körber
Friederike
F
Blankenburg
Markus
M
Mundlos
Stefan
S
Heller
Raoul
R
Hoffmann
Katrin
K
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*
C523021:CHRNA1 protein, human; C514767:CHRND protein, human; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic