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Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome

Sousa, Sérgio B
Author Sousa, Sérgio B ] Clinical and Molecular Genetics Unit, University College London (UCL) Institute of Child Health, London, UK. [2] Serviço de Genética Médica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
Jenkins, Dagan
Author Jenkins, Dagan ] Molecular Medicine Unit, UCL Institute of Child Health, London, UK. [2]
Chanudet, Estelle
Author Chanudet, Estelle ] Centre for Translational Genomics-GOSgene, UCL Institute of Child Health, London, UK. [2]
Tasseva, Guergana
Author Tasseva, Guergana ] Group on the Molecular and Cell Biology of Lipids, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. [2]
Ishida, Miho
Author Ishida, Miho Clinical and Molecular Genetics Unit, University College London (UCL) Institute of Child Health, London, UK
Anderson, Glenn
Author Anderson, Glenn Histopathology Department, Great Ormond Street Hospital for Children, London, UK
Docker, James
Author Docker, James Neural Development Unit, UCL Institute of Child Health, London, UK
Ryten, Mina
Author Ryten, Mina ] Reta Lila Weston Institute, UCL Institute of Neurology, London, UK. [2] Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
Sa, Joaquim
Author Sa, Joaquim Serviço de Genética Médica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
Saraiva, Jorge M
Author Saraiva, Jorge M ] Serviço de Genética Médica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal. [2] University Clinic of Pediatrics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Barnicoat, Angela
Author Barnicoat, Angela Clinical Genetics Department, Great Ormond Street Hospital, London, UK
Scott, Richard
Author Scott, Richard Clinical Genetics Department, Great Ormond Street Hospital, London, UK
Calder, Alistair
Author Calder, Alistair Radiology Department, Great Ormond Street Hospital, London, UK
Wattanasirichaigoon, Duangrurdee
Author Wattanasirichaigoon, Duangrurdee Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Chrzanowska, Krystyna
Author Chrzanowska, Krystyna Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland
Simandlová, Martina
Author Simandlová, Martina Department of Biology and Medical Genetics, University Hospital Motol and Second Faculty of Medicine, Prague, Czech Republic
Van Maldergem, Lionel
Author Van Maldergem, Lionel ] Centre de Génétique Humaine, Université de Franche-Comté, Besançon, France. [2] Cutis Laxa Study Group, University of Franche-Comté, Besancon, France
Stanier, Philip
Author Stanier, Philip Neural Development Unit, UCL Institute of Child Health, London, UK
Beales, Philip L
Author Beales, Philip L ] Molecular Medicine Unit, UCL Institute of Child Health, London, UK. [2] Centre for Translational Genomics-GOSgene, UCL Institute of Child Health, London, UK
Vance, Jean E
Author Vance, Jean E Group on the Molecular and Cell Biology of Lipids, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
Moore, Gudrun E
Author Moore, Gudrun E Clinical and Molecular Genetics Unit, University College London (UCL) Institute of Child Health, London, UK

Nature genetics. 2014 Jan ; 46 (1) : 70-6. [epub] 20131117

Nat Genet
ISSN 1546-1718 | 1061-4036
Source

Language English Country United States Media print-electronic

Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

Persistent link https://www.medvik.cz/link/pmid24241535

Grant support
G1001689 Medical Research Council - United Kingdom
Wellcome Trust - United Kingdom
G0802462 Medical Research Council - United Kingdom
HL-102926 NHLBI NIH HHS - United States
HL-102925 NHLBI NIH HHS - United States
HL-102923 NHLBI NIH HHS - United States
MR/K01417X/1 Medical Research Council - United Kingdom
HL-103010 NHLBI NIH HHS - United States
MR/L009978/1 Medical Research Council - United Kingdom
HL-102924 NHLBI NIH HHS - United States

PubMed 24241535
DOI 10.1038/ng.2829
PII: ng.2829
Knihovny.cz E-resources

MeSH
Zebrafish embryology genetics MeSH
Child MeSH
Embryo, Nonmammalian MeSH
Fibroblasts metabolism MeSH
Phosphatidylserines biosynthesis genetics MeSH
Hyperostosis MeSH
Cells, Cultured MeSH
Humans MeSH
Adolescent MeSH
Abnormalities, Multiple genetics MeSH
Molecular Sequence Data MeSH
Mutation * MeSH
Dwarfism MeSH
Syndrome MeSH
Nitrogenous Group Transferases genetics metabolism MeSH
Animals MeSH
Check Tag
Child MeSH
Humans MeSH
Adolescent MeSH
Male MeSH
Female MeSH
Animals MeSH
Publication type
Journal Article MeSH
Research Support, Non-U.S. Gov't MeSH
Research Support, N.I.H., Extramural MeSH
Names of Substances
Phosphatidylserines MeSH
phospholipid serine base exchange enzyme MeSH Browser
Nitrogenous Group Transferases MeSH

Lenz-Majewski syndrome (LMS) is a syndrome of intellectual disability and multiple congenital anomalies that features generalized craniotubular hyperostosis. By using whole-exome sequencing and selecting variants consistent with the predicted dominant de novo etiology of LMS, we identified causative heterozygous missense mutations in PTDSS1, which encodes phosphatidylserine synthase 1 (PSS1). PSS1 is one of two enzymes involved in the production of phosphatidylserine. Phosphatidylserine synthesis was increased in intact fibroblasts from affected individuals, and end-product inhibition of PSS1 by phosphatidylserine was markedly reduced. Therefore, these mutations cause a gain-of-function effect associated with regulatory dysfunction of PSS1. We have identified LMS as the first human disease, to our knowledge, caused by disrupted phosphatidylserine metabolism. Our results point to an unexplored link between phosphatidylserine synthesis and bone metabolism.

] Centre de Génétique Humaine Université de Franche Comté Besançon France [2] Cutis Laxa Study Group University of Franche Comté Besancon France

] Centre for Translational Genomics GOSgene UCL Institute of Child Health London UK [2]

] Clinical and Molecular Genetics Unit University College London Institute of Child Health London UK [2] Serviço de Genética Médica Hospital Pediátrico Centro Hospitalar e Universitário de Coimbra Coimbra Portugal

] Group on the Molecular and Cell Biology of Lipids Department of Medicine University of Alberta Edmonton Alberta Canada [2]

] Molecular Medicine Unit UCL Institute of Child Health London UK [2]

] Molecular Medicine Unit UCL Institute of Child Health London UK [2] Centre for Translational Genomics GOSgene UCL Institute of Child Health London UK

] Reta Lila Weston Institute UCL Institute of Neurology London UK [2] Department of Molecular Neuroscience UCL Institute of Neurology London UK

] Serviço de Genética Médica Hospital Pediátrico Centro Hospitalar e Universitário de Coimbra Coimbra Portugal [2] University Clinic of Pediatrics Faculty of Medicine University of Coimbra Coimbra Portugal

Clinical and Molecular Genetics Unit University College London Institute of Child Health London UK

Clinical Genetics Department Great Ormond Street Hospital London UK

Department of Biology and Medical Genetics University Hospital Motol and 2nd Faculty of Medicine Prague Czech Republic

Department of Medical Genetics Children's Memorial Health Institute Warsaw Poland