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.

Induction of Cullin 7 by DNA damage attenuates p53 function

“…We found that the substrate recognizing component of this complex, Fbx29, does not directly interact with p53, but associates indirectly with p53 in a Cul7-dependent manner. In agreement with our findings, the Cul7 domains responsible for p53 and FBX29 binding are not overlapping (25,27).…”

“…observed in mice deficient for other negative regulators of p53, as MDM2 and MDMX (30,32,33). In line with a positive role of Cul7 in unperturbed cell proliferation mutational inactivation of Cul7 causes the 3-M syndrome, an autorecessive form of dwarfism characterized by pre-and postnatal growth retardation (27). According to our results, it is possible that the increase in p53 activity, which may result from mutated, nonfunctional Cul7, contributes to the 3-M syndrome.…”

A large-scale mutation search reveals genetic heterogeneity in 3M syndrome

“…14 We have shown earlier that nonsense and missense CUL7 mutations (R1445X and H1464P) impaired the ability of CUL7 to recruit ROC1, suggesting that impaired ubiquitination may play a role in the pathogenesis of prenatal growth retardation in humans. 6 In addition, the association of pre-and postnatal growth retardation with skeletal changes in 3M syndrome suggests that CUL7 may play a specific role in the endochondral ossification process. In keeping with this, analysis of the femoral growth plate of the 3M foetus revealed an increased in chondrocyte density and a defect in matrix production in the resting and proliferative zones.…”

“…1 -5 Studying a series of 29 families, we have previously mapped the disease locus to chromosome 6p21.1, and identified diseasecausing mutations in the CUL7 gene. 6 Here, we report the molecular analysis of the CUL7 gene in a series of 33 additional cases and the identification of mutations in 23/33 cases including one paternal isodisomy of chromosome 6. The absence of CUL7 mutation in the other 10/33 cases and the exclusion of the 6p21.1 locus in consanguineous families support the genetic heterogeneity of the 3M syndrome.…”

New insights into the function of Cullin 3 in trophoblast invasion and migration

“…In addition, we have demonstrated that CUL1 promotes the invasion of human trophoblast cells and is significantly downregulated in the placentas from PE patients (Zhang et al 2013). Combined with the studies from other labs like the implication of Cullin 7 in 3-M syndrome and the Yakut short stature syndrome (Huber et al 2005, Maksimova et al 2007), characterized by pre-and post-natal growth retardation, we found that the Cullin family of proteins play very special roles during human placentation. To obtain a whole picture of the function of Cullin family proteins in human placenta development and pregnancy-related diseases, we further studied the roles of other Cullin family members, like CUL3, in placenta development.…”