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

Department of Pediatrics Faculty of Medicine Ramathibodi Hospital Mahidol University Bangkok Thailand

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

Histopathology Department Great Ormond Street Hospital for Children London UK

Neural Development Unit UCL Institute of Child Health London UK

Radiology Department Great Ormond Street Hospital London UK

Serviço de Genética Médica Hospital Pediátrico Centro Hospitalar e Universitário de Coimbra Coimbra Portugal

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J Biol Chem. 1986 May 5;261(13):5784-9 PubMed

J Biol Chem. 1998 Mar 27;273(13):7293-302 PubMed

Am J Med Genet. 2000 Mar 20;91(3):198-200 PubMed

Birth Defects Orig Artic Ser. 1974;10(12):133-6 PubMed

J Biol Chem. 1998 Jul 3;273(27):17199-205 PubMed

Am J Med Genet A. 2012 Sep;158A(9):2091-9 PubMed

Clin Dysmorphol. 2004 Jul;13(3):137-142 PubMed

J Inherit Metab Dis. 2011 Aug;34(4):907-16 PubMed

J Biol Chem. 2011 Jan 14;286(2):1061-73 PubMed

Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4199-203 PubMed

Biochim Biophys Acta. 2013 Mar;1831(3):543-54 PubMed

Development. 2006 Dec;133(23):4619-30 PubMed

Trends Genet. 2005 Nov;21(11):586-90 PubMed

J Cell Biochem. 2009 Jan 1;106(1):127-38 PubMed

J Biol Chem. 2008 Feb 15;283(7):3827-38 PubMed

J Immunol. 2010 Mar 15;184(6):3191-201 PubMed

Can J Biochem Physiol. 1959 Aug;37(8):911-7 PubMed

J Pediatr. 1977 Sep;91(3):417-21 PubMed

Nat Genet. 2009 Sep;41(9):1016-21 PubMed

Nature. 2010 Oct 28;467(7319):1061-73 PubMed

Am J Med Genet. 2000 Aug 14;93(4):335-8 PubMed

Am J Med Genet. 1989 Apr;32(4):470-4 PubMed

Radiology. 1983 Oct;149(1):129-31 PubMed

Nucleic Acids Res. 2001 Jan 1;29(1):308-11 PubMed

Lipids. 1966 Jan;1(1):85-6 PubMed

J Biol Chem. 2002 Dec 6;277(49):47701-8 PubMed

Am J Med Genet A. 2011 May;155A(5):943-68 PubMed

J Lipid Res. 2012 Feb;53(2):325-30 PubMed

J Biol Chem. 2001 Mar 16;276(11):8205-12 PubMed

J Clin Invest. 1976 May;57(5):1221-6 PubMed

Curr Treat Options Neurol. 2011 Oct;13(5):520-8 PubMed

J Can Assoc Radiol. 1974 Mar;25(1):22-33 PubMed

Sports Med. 2006;36(8):657-69 PubMed

Nat Genet. 2008 Mar;40(3):284-6 PubMed

Biochem J. 2009 Mar 1;418(2):421-9 PubMed

Molecules. 2009 Dec 22;14(12):5367-81 PubMed

Annu Rev Biophys. 2010;39:407-27 PubMed

Am J Dis Child. 1974 Jan;127(1):115-7 PubMed

Neurochem Res. 2003 Feb;28(2):195-214 PubMed

Biochem J. 1999 Aug 15;342 ( Pt 1):57-64 PubMed

Dev Biol. 2011 Feb 15;350(2):279-89 PubMed

J Biol Chem. 2008 May 9;283(19):12888-97 PubMed

Hum Genet. 2012 Nov;131(11):1761-73 PubMed

Biochem J. 2004 Aug 1;381(Pt 3):853-9 PubMed

J Biol Chem. 1999 Aug 20;274(34):23844-9 PubMed

Hum Mol Genet. 2009 Jun 15;18(12):2149-65 PubMed

J Biol Chem. 2000 Nov 3;275(44):34534-40 PubMed

Hum Mol Genet. 2011 Mar 1;20(5):948-61 PubMed

Oral Surg Oral Med Oral Pathol. 1969 Jan;27(1):20-6 PubMed

Cutis laxa and excessive bone growth due to de novo mutations in PTDSS1

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RefSeq
NM_014754, NP_055569

SWISSPROT
P48651