title: Identification of mutations in CUL7 in 3-M syndrome.
abstract: Intrauterine growth retardation is caused by maternal, fetal or placental factors that result in impaired endovascular trophoblast invasion and reduced placental perfusion. Although various causes of intrauterine growth retardation have been identified, most cases remain unexplained. Studying 29 families with 3-M syndrome (OMIM 273750), an autosomal recessive condition characterized by severe pre- and postnatal growth retardation, we first mapped the underlying gene to chromosome 6p21.1 and then identified 25 distinct mutations in the gene cullin 7 (CUL7). CUL7 assembles an E3 ubiquitin ligase complex containing Skp1, Fbx29 (also called Fbw8) and ROC1 and promotes ubiquitination. Using deletion analysis, we found that CUL7 uses its central region to interact with the Skp1-Fbx29 heterodimer. Functional studies indicated that the 3-M-associated CUL7 nonsense and missense mutations R1445X and H1464P, respectively, render CUL7 deficient in recruiting ROC1. These results suggest that impaired ubiquitination may have a role in the pathogenesis of intrauterine growth retardation in humans.
authors.affiliation: Université Paris-Descartes, Faculté de Médecine, INSERM, AP-HP, Hôpital Necker Enfants Malades, U393 and Department of Medical Genetics, 149 rue de Sèvres 75015, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Huber
authors.forename: Dora
authors.initials: D
authors.lastname: Dias-Santagata
authors.forename: Anna
authors.initials: A
authors.lastname: Glaser
authors.forename: James
authors.initials: J
authors.lastname: O'Sullivan
authors.forename: Raja
authors.initials: R
authors.lastname: Brauner
authors.forename: Kenneth
authors.initials: K
authors.lastname: Wu
authors.forename: Xinsong
authors.initials: X
authors.lastname: Xu
authors.forename: Kerra
authors.initials: K
authors.lastname: Pearce
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.forename: Maria Luisa Giovannucci
authors.initials: ML
authors.lastname: Uzielli
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dagoneau
authors.forename: Wassim
authors.initials: W
authors.lastname: Chemaitilly
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Heloisa
authors.initials: H
authors.lastname: Dos Santos
authors.forename: André
authors.initials: A
authors.lastname: Mégarbané
authors.forename: Gilles
authors.initials: G
authors.lastname: Morin
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: Raoul
authors.initials: R
authors.lastname: Hennekam
authors.forename: Ineke
authors.initials: I
authors.lastname: Van der Burgt
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Black
authors.forename: Peter E
authors.initials: PE
authors.lastname: Clayton
authors.forename: Andrew
authors.initials: A
authors.lastname: Read
authors.forename: Martine
authors.initials: M
authors.lastname: Le Merrer
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scambler
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Zhen-Qiang
authors.initials: ZQ
authors.lastname: Pan
authors.forename: Robin
authors.initials: R
authors.lastname: Winter
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism; D002648:Child; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D018389:Codon, Nonsense; D044842:Cullin Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D017384:Sequence Deletion; D013577:Syndrome
chemical_list: C506299:CUL7 protein, human; D002352:Carrier Proteins; D018389:Codon, Nonsense; D044842:Cullin Proteins; C479529:RBX1 protein, human; D044786:S-Phase Kinase-Associated Proteins; D044843:SKP Cullin F-Box Protein Ligases