TY - JOUR
T1 - Mutations in ECEL1 cause distal arthrogryposis type 5D
AU - McMillin, Margaret J.
AU - Below, Jennifer E.
AU - Shively, Kathryn M.
AU - Beck, Anita E.
AU - Gildersleeve, Heidi I.
AU - Pinner, Jason
AU - Gogola, Gloria R.
AU - Hecht, Jacqueline T.
AU - Grange, Dorothy K.
AU - Harris, David J.
AU - Earl, Dawn L.
AU - Jagadeesh, Sujatha
AU - Mehta, Sarju G.
AU - Robertson, Stephen P.
AU - Swanson, James M.
AU - Faustman, Elaine M.
AU - Mefford, Heather C.
AU - Shendure, Jay
AU - Nickerson, Deborah A.
AU - Bamshad, Michael J.
N1 - Funding Information:
We thank the families for their participation and support. Our work was supported in part by grants from the National Institutes of Health National Human Genome Research Institute (1U54HG006493 to M.B., D.N., and J.S.; 1RC2HG005608 to M.B., D.N., and J.S.; and 5RO1HG004316 to H.T.), the National Institute of Child Health and Development (HHSN27500503415C to J.M.S and HHSN267200700023C to E.M.F.), the Life Sciences Discovery Fund (2065508 and 0905001), and the Washington Research Foundation.
PY - 2013/1/10
Y1 - 2013/1/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84872321947&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2012.11.014
DO - 10.1016/j.ajhg.2012.11.014
M3 - Article
C2 - 23261301
AN - SCOPUS:84872321947
SN - 0002-9297
VL - 92
SP - 150
EP - 156
JO - American journal of human genetics
JF - American journal of human genetics
IS - 1
ER -