title: Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal gamma subunit.
abstract: Escobar syndrome is a form of arthrogryposis multiplex congenita and features joint contractures, pterygia, and respiratory distress. Similar findings occur in newborns exposed to nicotinergic acetylcholine receptor (AChR) antibodies from myasthenic mothers. We performed linkage studies in families with Escobar syndrome and identified eight mutations within the gamma -subunit gene (CHRNG) of the AChR. Our functional studies show that gamma -subunit mutations prevent the correct localization of the fetal AChR in human embryonic kidney-cell membranes and that the expression pattern in prenatal mice corresponds to the human clinical phenotype. AChRs have five subunits. Two alpha, one beta, and one delta subunit are always present. By switching gamma to epsilon subunits in late fetal development, fetal AChRs are gradually replaced by adult AChRs. Fetal and adult AChRs are essential for neuromuscular signal transduction. In addition, the fetal AChRs seem to be the guide for the primary encounter of axon and muscle. Because of this important function in organogenesis, human mutations in the gamma subunit were thought to be lethal, as they are in gamma -knockout mice. In contrast, many mutations in other subunits have been found to be viable but cause postnatally persisting or beginning myasthenic syndromes. We conclude that Escobar syndrome is an inherited fetal myasthenic disease that also affects neuromuscular organogenesis. Because gamma expression is restricted to early development, patients have no myasthenic symptoms later in life. This is the major difference from mutations in the other AChR subunits and the striking parallel to the symptoms found in neonates with arthrogryposis when maternal AChR auto-antibodies crossed the placenta and caused the transient inactivation of the AChR pathway.
authors.affiliation: Institute of Medical Genetics, Charite University Medical School, Humboldt University, 13353 Berlin, Germany. katrin.hoffmann.genetik@charite.de
authors.forename: Katrin
authors.initials: K
authors.lastname: Hoffmann
authors.forename: Juliane S
authors.initials: JS
authors.lastname: Muller
authors.forename: Sigmar
authors.initials: S
authors.lastname: Stricker
authors.forename: Andre
authors.initials: A
authors.lastname: Megarbane
authors.forename: Anna
authors.initials: A
authors.lastname: Rajab
authors.forename: Tom H
authors.initials: TH
authors.lastname: Lindner
authors.forename: Monika
authors.initials: M
authors.lastname: Cohen
authors.forename: Eliane
authors.initials: E
authors.lastname: Chouery
authors.forename: Lynn
authors.initials: L
authors.lastname: Adaimy
authors.forename: Ismat
authors.initials: I
authors.lastname: Ghanem
authors.forename: Valerie
authors.initials: V
authors.lastname: Delague
authors.forename: Eugen
authors.initials: E
authors.lastname: Boltshauser
authors.forename: Beril
authors.initials: B
authors.lastname: Talim
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.forename: Peter N
authors.initials: PN
authors.lastname: Robinson
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.forename: Christoph
authors.initials: C
authors.lastname: Hübner
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001176:Arthrogryposis / Q000196:embryology / Q000235:genetics / Q000503:physiopathology; D002648:Child; D005260:Female; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D020294:Myasthenic Syndromes, Congenital / Q000196:embryology / Q000235:genetics* / Q000503:physiopathology; D009469:Neuromuscular Junction / Q000196:embryology / Q000235:genetics / Q000503:physiopathology; D010375:Pedigree; D011247:Pregnancy; D021122:Protein Subunits / Q000235:genetics*; D011950:Receptors, Cholinergic / Q000235:genetics*
chemical_list: D021122:Protein Subunits; D011950:Receptors, Cholinergic