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.