Identification of mutations in CUL7 in 3-M syndrome

Article metrics


Intrauterine growth retardation is caused by maternal, fetal or placental factors that result in impaired endovascular trophoblast invasion and reduced placental perfusion1. 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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Clinical and radiological manifestations of 3-M and gloomy face syndromes.
Figure 2: Genetic mapping of the locus involved in 3-M syndrome.
Figure 3: Levels of CUL7 RNA expression.
Figure 4: Characterization of the interactions between CUL7 and Skp1-Fbx29.
Figure 5: Mutants CUL7-R1445X and CUL7-H1464P are devoid of ROC1 binding and ubiquitin ligase activities.

Accession codes




  1. 1

    Cetin, I. et al. Fetal growth restriction: a workshop report. Placenta 25, 753–757 (2004).

  2. 2

    Miller, J.D., McKusick, V., Malvaux, P., Tentamy, S.A. & Salinas, C.F. The 3-M syndrome: a heritable low birthweight dwarfism. Birth Defects Orig. Artic. Ser. 11, 39–47 (1975).

  3. 3

    Spranger, J., Opitz, J.M. & Nourmand, A. A new familial intrauterine growth retardation syndrome the “3 M syndrome”. Eur. J. Pediatr. 123, 115–124 (1976).

  4. 4

    Winter, R.M., Baraitser, M., Grant, D.B., Preece, M.A. & Hall, C.M. The 3M syndrome. J. Med. Genet. 21, 124–128 (1984).

  5. 5

    Hennekam, R.C., Biljlsma, J.B. & Spranger, J. Further delineation of the 3M syndrome with review of the literature. Am. J. Med. Genet. 28, 195–209 (1987).

  6. 6

    Van der Wal, G., Otten, B.J., Brunner, H.G. & Van der Burgt, I. 3M syndrome: description of 6 new patients with review of the literature. Clin. Dysmorphol. 10, 241–252 (2001).

  7. 7

    Mueller, R.F. et al. The 3-M syndrome: risk of intracerebral aneurysm? J. Med. Genet. 29, 425–427 (1992).

  8. 8

    Le Merrer, M., Brauner, R. & Maroteaux, P. Dwarfism with gloomy face: a new syndrome with features of 3-M syndrome. J. Med. Genet. 28, 186–191 (1991).

  9. 9

    Dias, D.C., Dolios, G., Wang, R. & Pan, Z.Q. CUL7: A DOC domain-containing cullin selectively binds Skp1.Fbx29 to form an SCF-like complex. Proc. Natl. Acad. Sci. USA 99, 16601–16606 (2002).

  10. 10

    Kohrman, D.C. & Imperiale, M.J. Simian virus 40 large T antigen stably complexes with a 185-kilodalton host protein. J. Virol. 66, 1752–1760 (1992).

  11. 11

    Daud, A.I., Lanson, N.A. Jr., Claycomb, W.C. & Field, L.J. Identification of SV40 large T-antigen-associated proteins in cardiomyocytes from transgenic mice. Am. J. Physiol. 264, H1693–H1700 (1993).

  12. 12

    Arai, T. et al. Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis. Proc. Natl. Acad. Sci. USA 100, 9855–9860 (2003).

  13. 13

    Pan, Z.Q., Kentsis, A., Dias, D.C., Yamoah, K. & Wu, K. Nedd8 on cullin: building an expressway to protein destruction. Oncogene 23, 1985–1997 (2004).

  14. 14

    Wu, K. et al. The SCF (HOS/beta-TRCP)-ROC1 E3 ubiquitin ligase utilizes two distinct domains within CUL1 for substrate targeting and ubiquitin ligation. Mol. Cell. Biol. 20, 1382–1393 (2000).

  15. 15

    Zheng, N. et al. Structure of the Cul1-Rbx1-Skp1-FboxSkp2 SCF ubiquitin ligase complex. Nature 416, 703–709 (2002).

  16. 16

    Charnock-Jones, D.S., Kaufmann, P. & Mayhew, T.M. Aspects of human foetoplacental vasculogenesis and angiogenesis I. Molecular regulation. Placenta 25, 103–113 (2004).

Download references


We thank M.H. Aguiar-Oliveira, B. Albrecht, H. Brunner, A. Janecke, H. Kingston, G. Mortier and E. Prott for collaboration and D. Vaiman for comments. Part of this work was supported by European Skeletal Dysplasia Network. Z.-Q.P. and R.W. are supported by Public Health Service grants. K.P. was funded by the London IDEAS genetics knowledge park, and P.J.S. was supported by the BDF Newlife and British Heart Foundation. J.O. was funded by the BDF Newlife. G.C.M.B. is a Wellcome Trust Senior Clinical Research Fellow. This manuscript is dedicated to the memory of Robin Winter.

Author information

Correspondence to Valérie Cormier-Daire.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Further reading