title: Mutation analysis of CHRNA1, CHRNB1, CHRND, and RAPSN genes in multiple pterygium syndrome/fetal akinesia patients.
abstract: Multiple pterygium syndromes (MPS) comprise a group of multiple congenital anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis). MPS are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal and nonlethal (Escobar) types. Previously, we and others reported that recessive mutations in the embryonal acetylcholine receptor g subunit (CHRNG) can cause both lethal and nonlethal MPS, thus demonstrating that pterygia resulted from fetal akinesia. We hypothesized that mutations in acetylcholine receptor-related genes might also result in a MPS/fetal akinesia phenotype and so we analyzed 15 cases of lethal MPS/fetal akinesia without CHRNG mutations for mutations in the CHRNA1, CHRNB1, CHRND, and rapsyn (RAPSN) genes. No CHRNA1, CHRNB1, or CHRND mutations were detected, but a homozygous RAPSN frameshift mutation, c.1177-1178delAA, was identified in a family with three children affected with lethal fetal akinesia sequence. Previously, RAPSN mutations have been reported in congenital myasthenia. Functional studies were consistent with the hypothesis that whereas incomplete loss of rapsyn function may cause congenital myasthenia, more severe loss of function can result in a lethal fetal akinesia phenotype.
authors.affiliation: Department of Medical and Molecular Genetics and WellChild Paediatric Research Centre, Division of Reproductive and Child Health, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Vogt
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Harrison
authors.forename: Hayley
authors.initials: H
authors.lastname: Spearman
authors.forename: Judy
authors.initials: J
authors.lastname: Cossins
authors.forename: Sascha
authors.initials: S
authors.lastname: Vermeer
authors.forename: Lambert Naudin
authors.initials: LN
authors.lastname: ten Cate
authors.forename: Neil V
authors.initials: NV
authors.lastname: Morgan
authors.forename: David
authors.initials: D
authors.lastname: Beeson
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D001176:Arthrogryposis / Q000235:genetics; D001483:Base Sequence; D002648:Child; D005315:Fetal Diseases / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics*; D011950:Receptors, Cholinergic / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics*; D013577:Syndrome
chemical_list: C523021:CHRNA1 protein, human; C519072:CHRNB1 protein, human; C514767:CHRND protein, human; D009124:Muscle Proteins; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic; C051609:peripheral membrane protein 43K