Identification of mutations in CUL7 in 3-M syndrome.
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.
Huber
Céline
C
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.
Dias-Santagata
Dora
D
Glaser
Anna
A
O'Sullivan
James
J
Brauner
Raja
R
Wu
Kenneth
K
Xu
Xinsong
X
Pearce
Kerra
K
Wang
Rong
R
Uzielli
Maria Luisa Giovannucci
ML
Dagoneau
Nathalie
N
Chemaitilly
Wassim
W
Superti-Furga
Andrea
A
Dos Santos
Heloisa
H
Mégarbané
André
A
Morin
Gilles
G
Gillessen-Kaesbach
Gabriele
G
Hennekam
Raoul
R
Van der Burgt
Ineke
I
Black
Graeme C M
GC
Clayton
Peter E
PE
Read
Andrew
A
Le Merrer
Martine
M
Scambler
Peter J
PJ
Munnich
Arnold
A
Pan
Zhen-Qiang
ZQ
Winter
Robin
R
Cormier-Daire
Valérie
V
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
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