Identification of mutations in CUL7 in 3-M syndrome

  title={Identification of mutations in CUL7 in 3-M syndrome},
  author={C{\'e}line Huber and Dora Dias-Santagata and Anna Glaser and James O’Sullivan and Raja Brauner and Kenneth Wu and Xinsong Xu and Kerra Pearce and Rong Wang and Maria Luisa Giovannucci Uzielli and Nathalie Dagoneau and Wassim Chemaitilly and Andrea Superti-Furga and Helo{\'i}sa G Dos Santos and Andr{\'e} M{\'e}garban{\'e} and Gilles Morin and G. Gillessen‐kaesbach and Raoul C.M. Hennekam and Ineke van der Burgt and Graeme C. M. Black and Peter Ellis Clayton and Andrew P. Read and Martine Le Merrer and Peter J. Scambler and Arnold Munnich and Zhen-Qiang Pan and Robin M. Winter and Val{\'e}rie Cormier-Daire},
  journal={Nature Genetics},
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… 

OBSL1 mutations in 3‐M syndrome are associated with a modulation of IGFBP2 and IGFBP5 expression levels

Real‐time quantitative PCR analysis for OBSL1, CUL7, IGFBP2, and IGFBP5, using cultured fibroblast RNAs from two patients with distinct OBSl1 mutations suggests that OBS L1 modulates the expression of IGFBP proteins.

The Genetics of 3-M Syndrome: Unravelling a Potential New Regulatory Growth Pathway

The physical interaction of OBSL1 with both CUL7 and CCDC8 and its potential role in the regulation of Cul7 expression suggest all three proteins are members of the same growth-regulatory pathway.

Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development.

It is shown here that CCDC8, derived from a retrotransposon Gag protein in placental mammals, exclusively localized on the plasma membrane and was phosphorylated by CK2 and GSK3, and LL5β, a plasma membrane protein that regulates cell migration, as a substrate of 3-M ligase.

Deletion of the CUL4B gene in a boy with mental retardation, minor facial anomalies, short stature, hypogonadism, and ataxia

A de novo deletion of the CUL4B gene is identified in a boy with syndromic mental retardation, minor facial anomalies, short stature, delayed puberty, hypogonadism, relative macrocephaly, gait ataxia, and pes cavus, all manifestations described previously in patients with Cul4B point mutations.

Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling.

The status of the GH-IGF axis evaluation could reflect a degree of GH resistance and/or IGF1 resistance, which is consistent with the signalling data in which the CUL7(-/-) cells showed impaired IGF1 signalling, CCDC8-/-) Cells showed impaired GH signalling and the OBSL1-/- cells showed impairment in both pathways.

Dissecting the genotype to phenotype relationships of genomic disorders

Over the last decade, major advances in the development and application of microarray-based comparative genomic hybridisation (aCGH) technology have significantly contributed to our understanding of

3-M syndrome: a growth disorder associated with IGF2 silencing

3-M syndrome is associated with a gene expression profile of reduced IGF2 expression and increased H19 expression similar to that found in Silver–Russell syndrome, and loss of autocrine IGF-II in the growth plate may be associated with the short stature seen in children with 3-M Syndrome.

Disruption of the Fbxw8 Gene Results in Pre- and Postnatal Growth Retardation in Mice

Results demonstrate that the FBXW8-CUL7 complex plays a significant role in growth control and results in significant reduction in embryo size and neonatal lethality in mice lacking Fbxw8 by gene trapping.



Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis

It is demonstrated that p185 forms an SCF-like complex with Skp1, Rbx1, Fbw6 (Fbx29), and FAP68 (FAP48, glomulin), which has recently been identified as a gene responsible for familial glomuvenous malformation.

A new familial intrauterine growth retardation syndrome the “3-M syndrome”

Clinical and genetic evidence suggests that the described intrauterine growth retardation syndrome is different from the Silver-Russell syndrome and presents an apparently “new” entity which has been designated 3-M syndrome.

Nedd8 on cullin: building an expressway to protein destruction

Increasing evidence indicates that removal of Nedd8 from its cullin targets, by the action of COP9 Signalosome and possibly other proteases, plays a significant role in the regulation of cullin-mediated proteolysis.

3-M syndrome: description of six new patients with review of the literature.

Six new patients with 3-M syndrome are described and compared with 28 cases from the literature, and it is proposed that calculating the metacarpal and vertebral indices can be used to measure and document this important diagnostic feature.

Further delineation of the 3-M syndrome with review of the literature.

The 3-M syndrome is a clinically recognizable disorder characterized by prenatal and postnatal growth retardation and a spectrum of consistent minor anomalies. Intelligence seems normal. Inheritance

CUL7: A DOC domain-containing cullin selectively binds Skp1⋅Fbx29 to form an SCF-like complex

This work describes an alternative mechanism for assembling an F-box protein-based E3 complex through a previously uncharacterized cullin, CUL7, identified by mass spectrometry as a ROC1-interacting protein.

Structure of the Cul1–Rbx1–Skp1–F boxSkp2 SCF ubiquitin ligase complex

The structure of the Cul1–Rbx1–Skp1–F boxSkp2 SCF complex suggests that Cul1 may contribute to catalysis through the positioning of the substrate and the ubiquitin-conjugating enzyme, and this model is supported by Cul1 mutations designed to eliminate the rigidity of the scaffold.

The SCFHOS/β-TRCP-ROC1 E3 Ubiquitin Ligase Utilizes Two Distinct Domains within CUL1 for Substrate Targeting and Ubiquitin Ligation

A purified ubiquitination system capable of rapidly catalyzing the covalent linkage of polyubiquitin chains onto a model substrate, phosphorylated IκBα, is described and the mode of action of SCF-ROC1 is suggested, where CUL1 serves as a dual-function molecule that recruits an F-box protein for substrate targeting through Skp1 at its N terminus.

Identification of SV40 large T-antigen-associated proteins in cardiomyocytes from transgenic mice.

Several proteins that cross-reacted with either anti-T-antigen or anti-p53 antibodies were identified and may be important constituents of the cardiomyocyte cell cycle, as well as potential cellular targets for myocardial regeneration.