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

Nat Genet. 2014 Jan;46(1):70-6. doi: 10.1038/ng.2829.

Sérgio B Sousa ¹, Dagan Jenkins ², Estelle Chanudet ³, Guergana Tasseva ⁴, Miho Ishida ⁵, Glenn Anderson ⁶, James Docker ⁷, Mina Ryten ⁸, Joaquim Sa ⁹, Jorge M Saraiva ¹⁰, Angela Barnicoat ¹¹, Richard Scott ¹¹, Alistair Calder ¹², Duangrurdee Wattanasirichaigoon ¹³, Krystyna Chrzanowska ¹⁴, Martina Simandlová ¹⁵, Lionel Van Maldergem ¹⁶, Philip Stanier ⁷, Philip L Beales ¹⁷, Jean E Vance ¹⁸, Gudrun E Moore ⁵

Affiliations

1 1] 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.
2 1] Molecular Medicine Unit, UCL Institute of Child Health, London, UK. [2].
3 1] Centre for Translational Genomics-GOSgene, UCL Institute of Child Health, London, UK. [2].
4 1] Group on the Molecular and Cell Biology of Lipids, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. [2].
5 Clinical and Molecular Genetics Unit, University College London (UCL) Institute of Child Health, London, UK.
6 Histopathology Department, Great Ormond Street Hospital for Children, London, UK.
7 Neural Development Unit, UCL Institute of Child Health, London, UK.
8 1] Reta Lila Weston Institute, UCL Institute of Neurology, London, UK. [2] Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
9 Serviço de Genética Médica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
10 1] 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.
11 Clinical Genetics Department, Great Ormond Street Hospital, London, UK.
12 Radiology Department, Great Ormond Street Hospital, London, UK.
13 Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
14 Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland.
15 Department of Biology and Medical Genetics, University Hospital Motol and Second Faculty of Medicine, Prague, Czech Republic.
16 1] Centre de Génétique Humaine, Université de Franche-Comté, Besançon, France. [2] Cutis Laxa Study Group, University of Franche-Comté, Besancon, France.
17 1] Molecular Medicine Unit, UCL Institute of Child Health, London, UK. [2] Centre for Translational Genomics-GOSgene, UCL Institute of Child Health, London, UK.
18 Group on the Molecular and Cell Biology of Lipids, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.

PMID: 24241535 DOI: 10.1038/ng.2829

Abstract

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.

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