title: Truncating CHRNG mutations associated with interfamilial variability of the severity of the Escobar variant of multiple pterygium syndrome.
abstract: In humans, muscle-specific nicotinergic acetylcholine receptor (AChR) is a transmembrane protein with five different subunits, coded by CHRNA1, CHRNB, CHRND and CHRNG/CHRNE. The gamma subunit of AChR encoded by CHRNG is expressed during early foetal development, whereas in the adult, the γ subunit is replaced by a ε subunit. Mutations in the CHRNG encoding the embryonal acetylcholine receptor may cause the non-lethal Escobar variant (EVMPS) and lethal form (LMPS) of multiple pterygium syndrome. The MPS is a condition characterised by prenatal growth failure with pterygium and akinesia leading to muscle weakness and severe congenital contractures, as well as scoliosis.
  
  
  
  Our whole exome sequencing studies have identified one novel and two previously reported homozygous mutations in CHRNG in three families affected by non-lethal EVMPS. The mutations consist of deletion of two nucleotides, cause a frameshift predicted to result in premature termination of the foetally expressed gamma subunit of the AChR.
  
  
  
  Our data suggest that severity of the phenotype varies significantly both within and between families with MPS and that there is no apparent correlation between mutation position and clinical phenotype. Although individuals with CHRNG mutations can survive, there is an increased frequency of abortions and stillbirth in their families. Furthermore, genetic background and environmental modifiers might be of significance for decisiveness of the lethal spectrum, rather than the state of the mutation per se. Detailed clinical examination of our patients further indicates the changing phenotype from infancy to childhood.
authors.affiliation: Kariminejad-Najmabadi Pathology & Genetics Centre, Tehran, Iran.
authors.forename: Ariana
authors.initials: A
authors.lastname: Kariminejad
authors.affiliation: Kariminejad-Najmabadi Pathology & Genetics Centre, Tehran, Iran.
authors.forename: Navid
authors.initials: N
authors.lastname: Almadani
authors.affiliation: Mehrgan Genetics Centre, Sari, Iran.
authors.forename: Atefeh
authors.initials: A
authors.lastname: Khoshaeen
authors.affiliation: Systems Biology Research Centre, School of Bioscience, University of Skovde, SE-541 28, Skovde, Sweden.
authors.forename: Bjorn
authors.initials: B
authors.lastname: Olsson
authors.affiliation: Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, SE-413 45, Gothenburg, Sweden.
authors.forename: Ali-Reza
authors.initials: AR
authors.lastname: Moslemi
authors.affiliation: Systems Biology Research Centre, School of Bioscience, University of Skovde, SE-541 28, Skovde, Sweden. homa.tajsharghi@his.se.|Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, SE-413 45, Gothenburg, Sweden. homa.tajsharghi@his.se.
authors.forename: Homa
authors.initials: H
authors.lastname: Tajsharghi
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D011247:Pregnancy; D011978:Receptors, Nicotinic / Q000235:genetics*; D012868:Skin Abnormalities / Q000235:genetics*
chemical_list: C539275:CHRNG protein, human; D011978:Receptors, Nicotinic