title: Mutations in ECEL1 cause distal arthrogryposis type 5D.
abstract: Distal arthrogryposis (DA) syndromes are the most common of the heritable congenital-contracture disorders, and ~50% of cases are caused by mutations in genes that encode contractile proteins of skeletal myofibers. DA type 5D (DA5D) is a rare, autosomal-recessive DA previously defined by us and is characterized by congenital contractures of the hands and feet, along with distinctive facial features, including ptosis. We used linkage analysis and whole-genome sequencing of a multiplex consanguineous family to identify in endothelin-converting enzyme-like 1 (ECEL1) mutations that result in DA5D. Evaluation of a total of seven families affected by DA5D revealed in five families ECEL1 mutations that explain ~70% of cases overall. ECEL1 encodes a neuronal endopeptidase and is expressed in the brain and peripheral nerves. Mice deficient in Ecel1 exhibit perturbed terminal branching of motor neurons to the endplate of skeletal muscles, resulting in poor formation of the neuromuscular junction. Our results distinguish a second developmental pathway that causes congenital-contracture syndromes.
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: McMillin
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Below
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Shively
authors.forename: Anita E
authors.initials: AE
authors.lastname: Beck
authors.forename: Heidi I
authors.initials: HI
authors.lastname: Gildersleeve
authors.forename: Jason
authors.initials: J
authors.lastname: Pinner
authors.forename: Gloria R
authors.initials: GR
authors.lastname: Gogola
authors.forename: Jacqueline T
authors.initials: JT
authors.lastname: Hecht
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Grange
authors.forename: David J
authors.initials: DJ
authors.lastname: Harris
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Earl
authors.forename: Sujatha
authors.initials: S
authors.lastname: Jagadeesh
authors.forename: Sarju G
authors.initials: SG
authors.lastname: Mehta
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Robertson
authors.forename: James M
authors.initials: JM
authors.lastname: Swanson
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Faustman
authors.forename: Heather C
authors.initials: HC
authors.lastname: Mefford
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
mesh_terms: D001176:Arthrogryposis / Q000235:genetics*; D003241:Consanguinity; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics*; D009154:Mutation; D017422:Sequence Analysis, DNA
chemical_list: C492359:ECEL1 protein, human; D008666:Metalloendopeptidases