title: DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III.
abstract: Jeune asphyxiating thoracic dystrophy (ATD) is an autosomal-recessive chondrodysplasia characterized by short ribs and a narrow thorax, short long bones, inconstant polydactyly, and trident acetabular roof. ATD is closely related to the short rib polydactyly syndrome (SRP) type III, which is a more severe condition characterized by early prenatal expression and lethality and variable malformations. We first excluded IFT80 in a series of 26 fetuses and children belonging to 14 families diagnosed with either ATD or SRP type III. Studying a consanguineous family from Morocco, we mapped an ATD gene to chromosome 11q14.3-q23.1 in a 20.4 Mb region and identified homozygous mutations in the cytoplasmic dynein 2 heavy chain 1 (DYNC2H1) gene in the affected children. Compound heterozygosity for DYNC2H1 mutations was also identified in four additional families. Among the five families, 3/5 were diagnosed with ATD and 2/5 included pregnancies terminated for SRP type III. DYNC2H1 is a component of a cytoplasmic dynein complex and is directly involved in the generation and maintenance of cilia. From this study, we conclude that ATD and SRP type III are variants of a single disorder belonging to the ciliopathy group.
authors.affiliation: Département de Génétique, Unité INSERM U781, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, 75015 Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dagoneau
authors.forename: Marie
authors.initials: M
authors.lastname: Goulet
authors.forename: David
authors.initials: D
authors.lastname: Geneviève
authors.forename: Yves
authors.initials: Y
authors.lastname: Sznajer
authors.forename: Jelena
authors.initials: J
authors.lastname: Martinovic
authors.forename: Sarah
authors.initials: S
authors.lastname: Smithson
authors.forename: Céline
authors.initials: C
authors.lastname: Huber
authors.forename: Geneviève
authors.initials: G
authors.lastname: Baujat
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Flori
authors.forename: Laura
authors.initials: L
authors.lastname: Tecco
authors.forename: Denise
authors.initials: D
authors.lastname: Cavalcanti
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Delezoide
authors.forename: Valérie
authors.initials: V
authors.lastname: Serre
authors.forename: Martine
authors.initials: M
authors.lastname: Le Merrer
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D056445:Cytoplasmic Dyneins; D004398:Dyneins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D010375:Pedigree; D012131:Respiratory Insufficiency / Q000235:genetics*; D012779:Short Rib-Polydactyly Syndrome / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; C099883:DYNC2H1 protein, human; C530863:IFT80 protein, human; D056445:Cytoplasmic Dyneins; D004398:Dyneins