Human Molecular Genetics Advance Access originally published online on April 14, 2008
Human Molecular Genetics 2008 17(14):2172-2180; doi:10.1093/hmg/ddn116
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The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity
1 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, USA 2 Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of City University of New York, New York, USA 3 Instituto de Genética, Universidad Nacional de Colombia, Bogotá, Colombia 4 Institute of Human Genetics, International Centre for Life, Newcastle University, Newcastle upon Tyne, UK 5 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, USA 6 Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan 7 Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey 8 Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark 9 Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London, UK 10 Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 11 Genetics and Molecular Medicine Unit, Department of Paediatrics, University of Florence, Florence, Italy 12 Department of Pediatrics, Cooper University Hospital/Robert Wood Johnson Medical School, Camden, USA 13 Department of Clinical Genetics, University Hospital, Lille, France 14 Department of Clinical Genetics, Oxford Radcliffe Hospitals National Health Service (NHS) Trust, Churchill Hospital, Oxford, UK 15 S.C. Genetica Umana, Ospedali Galliera, Genova, Italy 16 Department of Human Genetics, Ruhr University of Bochum, Bochum, Germany 17 Department of Pediatrics, Tampere University Hospital, Tampere, Finland 18 Department of Human Genetics, Hadassah Hebrew University Hospital, Jerusalem, Israel 19 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, USA
* To whom correspondence should be addressed at: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, 1428 Madison Avenue, Atran AB1-47, New York, NY 10029-6574, USA. Tel: +1 2122413504; Fax: +1 2122417112; Email: ethylin.jabs{at}mssm.edu
Received February 25, 2008; Accepted April 8, 2008
Roberts syndrome/SC phocomelia (RBS) is an autosomal recessive disorder with growth retardation, craniofacial abnormalities and limb reduction. Cellular alterations in RBS include lack of cohesion at the heterochromatic regions around centromeres and the long arm of the Y chromosome, reduced growth capacity, and hypersensitivity to DNA damaging agents. RBS is caused by mutations in ESCO2, which encodes a protein belonging to the highly conserved Eco1/Ctf7 family of acetyltransferases that is involved in regulating sister chromatid cohesion. We identified 10 new mutations expanding the number to 26 known ESCO2 mutations. We observed that these mutations result in complete or partial loss of the acetyltransferase domain except for the only missense mutation that occurs in this domain (c.1615T>G, W539G). To investigate the mechanism underlying RBS, we analyzed ESCO2 mutations for their effect on enzymatic activity and cellular phenotype. We found that ESCO2 W539G results in loss of autoacetyltransferase activity. The cellular phenotype produced by this mutation causes cohesion defects, proliferation capacity reduction and mitomycin C sensitivity equivalent to those produced by frameshift and nonsense mutations associated with decreased levels of mRNA and absence of protein. We found decreased proliferation capacity in RBS cell lines associated with cell death, but not with increased cell cycle duration, which could be a factor in the development of phocomelia and cleft palate in RBS. In summary, we provide the first evidence that loss of acetyltransferase activity contributes to the pathogenesis of RBS, underscoring the essential role of the enzymatic activity of the Eco1p family of proteins.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.